No disease engenders more of an emotional response than AIDS (Acquired Immune Deficiency Syndrome). It was not that long ago that the disease was whispered in health circles. Thanks to the testimonials of many brave individuals, AIDS can be discussed in open forums where elusive clues to the identification and treatment of the disease can be sought. HIV-1 is the etiologic agent of AIDS. HIV-2 is a similar virus strain which can infect man. The virus appears to be less aggressive than HIV-2 and the disease progression may be slower. Furthermore, it is less sensitive to serum antibodies.
The disease was first documented in the United States in 1978 but it was not until 1981 that the CDC published initial reports of the syndrome.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
Sexually, parenterally, mother to infant
Casual sex is the most frequent mode of transmission
HIV-1 infection incidence among persons with hemophilia in the United States and western Europe, 1978-1990. Multicenter Hemophilia Cohort Study.
Kroner BL, Rosenberg PS, Aledort LM, Alvord WG, Goedert JJ.
Research Triangle Institute, Rockville, MD 20852.
J Acquir Immune Defic Syndr 1994 Mar;7(3):279-86 Abstract quote
We studied human immunodeficiency virus type 1 (HIV-1) infection incidence over time in a 16-center cohort of hemophiliacs in the United States and Europe and estimated the most likely date of seroconversion for all seropositive subjects.
Five U.S. centers enrolled subjects independent of HIV-1 status, whereas 11 centers preferentially included seropositive subjects. We obtained unbiased estimates of HIV-1 infection incidence rates from the five centers and estimated dates of seroconversion from the distribution seen among seropositives from all centers. In the five-center cohort, infection incidence began in 1978, peaked in October 1982 at 22 infections per 100 person-years at risk, and declined to 4 per 100 person-years by July 1984. Few infections occurred after 1987, and by that time, 50% of the cohort had become infected. Median seroconversion dates for subgroups of all seropositives ranged from July 1980 to December 1983, depending on the dose and type of factor concentrate. Median dates in Europe ranged from September 1981 to March 1983 and reflected the use of products manufactured from American plasma. Infection incidence apparently peaked about the same time that public health interventions were introduced to reduce transmission.
These interventions, including heat treatment of factor concentrates and deferral of high-risk donors, have prevented HIV-1 infection from becoming endemic among younger birth cohorts of persons with hemophilia.
42% of HIV-positive patients have not disclosed their infection to their partners and 58% of seropositive adults failed to consistently use condoms
Women have a higher risk of infection since they have a greater risk of encountering an infected partner
Kissing or contact with saliva is theoretically possible and at least one case has been documented
Parenteral Accounts for 36% of all adult infections
In health care workers, penetrating injury is the most common cause
Mother to infant
HIV can cross the placenta as early as 15 weeks into the pregnancy resulting in infants born to HIV-positive mothers at 30% risk for being positive at birth
Risk of transmission increases with pregnant woman having:
Low CD4 count
Placental membrane inflammation
Late stage disease
Prenatal prophylaxis with AZT has been to shown to block transmission
30 million HIV positive people worldwide
In 1997, 2.3 million people died from AIDS
AGE RANGE-MEDIAN Leading cause of death among 25-44 years old
11% of total US AIDS population in 1996 were older than 50 years
GEOGRAPHY 89% of all infected people reside in sub-Saharan Africa and Asia
HIV disease progression in 854 women and men infected through injecting drug use and heterosexual sex and followed for up to nine years from seroconversion. Italian Seroconversion Study.
Cozzi Lepri A, Pezzotti P, Dorrucci M, Phillips AN, Rezza G.
Istituto Superiore di Sanita, Laboratorio di Epidemiologia e Biostatistica, Centro Operativo AIDS, Rome, Italy.
BMJ 1994 Dec 10;309(6968):1537-42 Abstract quote
OBJECTIVE--To compare the progression of HIV-1 infection in men and women followed up for up to nine years after an accurately estimated date of seroconversion.
DESIGN--Prospective observational study.
SETTING--16 HIV outpatient clinics across Italy.
SUBJECTS--321 women and 533 men infected with HIV through injecting drug use or heterosexual sex and with accurately estimated dates of seroconversion.
MAIN OUTCOME MEASURES--Progression to severe CD4 lymphocytopenia (CD4 lymphocyte count < 200 x 10(6)/l), development of AIDS defining diseases, and death from AIDS.
RESULTS--Thirty two women and 67 men developed AIDS at Kaplan-Meier progression rates of 25% (95% confidence interval 13.8% to 35.5%) and 23% (15.6% to 30.4%), respectively, 7 years after seroconversion. In a Cox proportional hazards model the relative hazard was 0.93 (that is, a slightly lower hazard in women) before and 1.10 (0.70 to 1.72) after adjusting for age, HIV exposure group, and year of seroconversion. When CD4 lymphocytopenia and death from AIDS were used as end points the results were similar, with adjusted relative hazards of 0.95 (0.63 to 1.42) and 0.72 (0.48 to 1.79) respectively. In both women and men the risk of developing AIDS before the CD4 lymphocyte count had declined below 200 x 10(6)/l was small (3% in women, 6% in men). The estimated median count at which AIDS developed in women (34 x 10(6)/l; 10 x 10(6) to 44 x 10(6)) was similar to that for men (44 x 10(6)/l; 22 x 10(6) to 60 x 10(6)).
CONCLUSION--There seems to be little evidence for appreciable differences in the natural course of HIV infection between men and women followed up from the time of seroconversion.
DISEASE ASSOCIATIONS CHARACTERIZATION ALOPECIA
- J Cutan Pathol. 2006 Oct;33(10):667-71 Abstract quote
Background: Diffuse alopecia occurs in almost 7% of HIV-1-infected patients. Telogen effluvium is the main pathogenic mechanism involved. Apoptotic keratinocytes in the outer root sheath at bulge level was described as the most characteristic histopathologic finding of this kind of hair loss.
Methods: A case-control study was conducted to investigate the occurrence of apoptosis of follicular stem cells at the bulge in diffuse alopecia of HIV-1 infection. We applied a double-staining procedure to transverse scalp sections from 15 HIV-1-infected patients and 12 controls, with the monoclonal antibody anticytokeratin 19 as stem cell marker and TUNEL technique to identify apoptosis.
Results: Eighty percent of cases and 25% of controls presented at least one double-stained follicle. The proportion of positive follicles per section was 48% (+/-7%) for cases and 26% (+/-13%) for controls.
Conclusion: Our study demonstrated that diffuse alopecia related to HIV-1 infection represents a hair cycle disturbance and that part of the follicular stem cell population become apoptotic in a higher proportion than normal subjects. We found no cytotoxic folliculitis. Owing to its cell-cycle interaction and caspase-induction capacities, we propose HIV-1 viral protein R as a possible follicular stem cell apoptosis inductor.
Non-acquired immunodeficiency syndrome-defining malignancies in patients infected with human immunodeficiency virus.
Demopoulos BP, Vamvakas E, Ehrlich JE, Demopoulos R.
Weill Medical College of Cornell University, New York, NY, USA.
Arch Pathol Lab Med 2003 May;127(5):589-92 Abstract quote
CONTEXT: Non-acquired immunodeficiency syndrome (AIDS)-defining malignancies that occur in patients infected with human immunodeficiency virus (HIV) and the demographics and pathologic features associated with these malignancies have not been completely defined.
OBJECTIVE: This study describes the age of onset of malignant disease in patients seropositive for HIV and in control patients presumed to be negative for HIV, but with the same primary site. We compare the demographics and histopathology for both groups.
DESIGN: From 1993 to 1997, 57 cases involving HIV-positive patients with malignancies from 16 primary sites were recorded in the Cancer Registry files at Bellevue Hospital; 519 cases involving patients negative for HIV were recorded during this same period. We compared the age at diagnosis, sex, race, tumor histology, stage, and grade between these 2 groups.
RESULTS: The average age of HIV-positive patients was 47.6 years, compared with 60.3 years in the control group (P <.001). When the 16 cancer sites were compared individually, HIV-positive patients were significantly younger at onset of lung (HIV-positive patients/control group) (19/245), skin (11/77), penile (3/5), laryngeal (3/18), tongue (5/16), and colorectal (2/38) carcinomas. Patients infected with HIV had a more frequent history of smoking (41/328; P =.04) and illicit drug use (30/49; P <.001). The HIV-positive patients also were found to have a lower clinical stage of disease, compared with controls, largely due to the higher prevalence of stage 0 tumors (13/46; P =.01).
CONCLUSIONS: The finding of younger age at diagnosis in HIV-positive compared to presumed HIV-negative patients may be related in part to earlier detection, as well as preexisting immunosuppression. The specific sites for which a significant difference in age between the HIV-positive and control cases was observed may be related to the mechanisms of immunosurveillance in parts of the body that have ready access to the outside environment. Knowledge of younger age of onset for these malignancies should prompt closer physical examination of these sites by clinicians.
Risk of cancer in children with AIDS. AIDS-Cancer Match Registry Study Group.
Biggar RJ, Frisch M, Goedert JJ.
VEB/NCI, 6120 Executive Blvd, Room 8014, Bethesda, MD 20852.
JAMA 2000 Jul 12;284(2):205-9 Abstract quote
CONTEXT: Population-based data on cancers associated with acquired immunodeficiency syndrome (AIDS) in children are lacking.
OBJECTIVE: To determine risk of pediatric AIDS-associated cancers.
DESIGN, SETTING, AND PARTICIPANTS: Using records from 11 locations in the United States for varying periods between 1978 and 1996, we linked data for children aged 14 years and younger at AIDS diagnosis to local cancer registry data.
MAIN OUTCOME MEASURES: Cancer frequency and, in the 2-year post-AIDS onset period, cancer incidence and relative risk (RR; measured as standardized incidence ratio), by cancer type.
RESULTS: Among 4954 children with AIDS, 124 (2.5%) were identified as having cancer before, at, or after AIDS onset, including 100 cases of non-Hodgkin lymphoma (NHL), 8 of Kaposi sarcoma (KS), 4 of leiomyosarcoma, and 2 of Hodgkin disease; there were 10 other or unspecified cancers. Expected numbers for all cancers identified in the study sample, based on population rates (using area-specific registry data), were less than 1. In the first 2 years after AIDS diagnosis (5485 person-years), NHL incidence was 510 per 100,000 person-years (RR, 651; 95% confidence interval [CI], 432-941). Median time for developing NHL after AIDS diagnosis was 14 months (range, 3-107 months). The most common type of NHL was Burkitt lymphoma. However, the risk of primary brain lymphoma (91 per 100,000 person-years) was especially high (RR, 7143; 95% CI, 2321-16,692), and 4 cases were diagnosed more than 2 years (range, 37-98 months) after AIDS onset. Leiomyosarcomas also tended to occur several years after AIDS onset, with 3 of the 4 cases occurring 33 to 76 months after AIDS diagnosis, whereas KS was reported only at or within 2 years of AIDS diagnosis. Hodgkin disease risk was also significantly increased (RR, 62; 95% CI, 2-342).
CONCLUSIONS: The spectrum of AIDS-associated pediatric cancers resembled that seen in adults, with the addition of leiomyosarcoma. Both primary brain lymphomas and leiomyosarcomas tended to occur in children surviving several years after AIDS onset. Because the expected numbers of these cancers in this population were less than 1 and because of the small numbers of some types of observed cancers, the RR estimates are imprecise and caution is warranted in their interpretation
Prevalence and predictors of skin disease in the Women's Interagency HIV Study (WIHS)
Paradi Mirmirani, etal.
J Am Acad Dermatol 2001;44:785-8 Abstract quote
Objective: We attempted to determine the prevalence and predictors of skin disease in a cohort of women with and at risk for HIV infection.
Methods: We analyzed baseline data from a multicenter longitudinal study of HIV infection in women.
Results: A total of 2018 HIV-infected women and 557 HIV-uninfected women were included in this analysis. Skin abnormalities were reported more frequently among HIV-infected than uninfected women (63% vs 44%, respectively; odds ratio [OR] 2.10; 95% confidence interval [95% CI], 1.74-2.54). Infected women were also more likely to have more than 2 skin diagnoses (OR, 3.27; 95% CI, 1.31-8.16). Folliculitis, seborrheic dermatitis, herpes zoster, and onychomycosis were more common among HIV-infected women (P < .05). Independent predictors of abnormal findings on skin examination in the infected women were African American race (OR, 1.38; 95% CI, 1.07-1.77), injection drug use (OR, 2.74; 95% CI, 2.11-3.57), CD4+ count less than 50 (OR, 1.68; 95% CI, 1.17-2.42), and high viral loads (100,000-499,999 = OR, 1.77; 95% CI, 1.32-2.37; >499,999 = OR, 2.15; 95% CI, 1.42-3.27).
Conclusion: HIV infection was associated with a greater number of skin abnormalities and with specific dermatologic diagnoses. Skin abnormalities were also more common among women with CD4+ cell depletion or higher viral load.
HIV and alcohol use: Consequences of comorbidity
Am Clin Lab 2001;20:13-16
Poor compliance with medications
Alcohol upregulates CXCR4 chemokine receptor leading to enhanced HIV replication in quiescent lymphocytes
Alcohol reactivates HIV-1 infected latent peripheral blood lymphocytes and increases viral replication
Alcohol inhibits thymidine kinase activity essential for activation of AZT
AIDS-related non-Hodgkin's lymphomas: From pathology and molecular pathogenesis to treatment.
Division of Pathology and Scientific Direction, Centro di Riferimento Oncologico-IRCCS, National Cancer Institute, Aviano, Italy.
Hum Pathol 2002 Apr;33(4):392-404 Abstract quote
In the highly active antiretroviral therapy (HAART) era, AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and their treatment still represent an open issue, because HAART may not be sufficient to prevent the development of NHL. The present spectrum of AIDS-NHL includes systemic lymphomas, primary central nervous system lymphomas, and 2 rare entities, primary effusion lymphomas (PEL) and plasmablastic lymphomas of the oral cavity.
The vast majority of systemic AIDS-NHL belongs to 3 high-grade B-cell lymphomas: Burkitt's lymphoma (BL), immunoblastic lymphoma (IBL), and large-cell lymphoma (LCL). The pathologic heterogeneity of AIDS-NHL is correlated with the heterogeneity of the molecular lesions associated with these lymphomas. The molecular lesions associated with AIDS-BL involve activation of c-MYC inactivation of p53, and infection by Epstein-Barr virus (EBV). EBV infection occurs in 40% of LCL cases and in 90% of IBL cases. Rearrangements of BCL-6 are detected in 20% of AIDS-LCL cases. In the presence of EBV infection, BCL-6 expressing AIDS-LCL fails to express the latent membrane protein 1 (LMP1) antigen. Conversely, AIDS-IBL are characterized by absent BCL-6 expression, absence of BCL-6 rearrangements, and frequent expression of LMP1. Consistently, the molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-NHL vary substantially in different clinicopathologic categories of the disease. The marked degree of biologic heterogeneity of AIDS-NHL is highlighted by their histogenetic differences, because AIDS-NHL are related to distinct B cell subsets (ie, germinal center [GC] or post-GC B cells). The phenotypic pattern of AIDS-BL and systemic AIDS-LCL closely reflects B cells residing in the GC, namely centroblasts and centrocytes. Conversely, the phenotype of AIDS-IBL, either systemic or localized primarily to the central nervous system, and AIDS-PEL reflects post-GC B cells in all cases.
New information on the molecular and virologic pathogenesis of AIDS-NHL may serve as a point of attack for pathogenic-driven therapies. Moreover, a greater knowledge of other biologic features of these tumors may help investigators identify new potential targets for "intelligent" therapies.
Altered Clinical Course of Malignant Melanoma in HIV-Positive Patients.
Rodrigues LK, Klencke BJ, Vin-Christian K, Berger TG, Crawford RI, Miller JR 3rd, Ferreira CM, Nosrati M, Kashani-Sabet M.
University of California, San Francisco, Melanoma Center, UCSF Comprehensive Cancer Center, 1600 Divisadero St, San Francisco, CA 94115.
Arch Dermatol 2002 Jun;138(6):765-70 Abstract quote
OBJECTIVE: To determine whether the natural history of melanoma is different in patients who test positive for human immunodeficiency virus (HIV) compared with matched control subjects.
DESIGN: Retrospective cohort analysis.
SETTING: Ambulatory care at 2 university-affiliated medical centers. PATIENTS: Each HIV-positive melanoma patient (n = 17) was randomly matched with 2 HIV-negative patients (HIV status unknown, but without risk factors for HIV) based on the melanoma subtype, tumor thickness, Clark level, tumor location, and sex and age of the patient.
MAIN OUTCOME MEASURES: Disease-free survival and overall survival of HIV-positive and HIV-negative melanoma patients were compared using a matched-pairs analysis. CD4 cell counts were recorded at the time of melanoma diagnosis and disease recurrence.
RESULTS: Melanoma patients who were HIV positive had a significantly shorter disease-free survival (P =.03) and overall survival (P =.045) compared with HIV-negative melanoma patients by matched-pairs analysis. There was an inverse relationship between CD4 cell counts and time to first melanoma recurrence.
CONCLUSIONS: The natural history of malignant melanoma in HIV-positive patients is more aggressive compared with matched HIV-negative melanoma patients. Altered immune response and comorbid disease may play a role in the poor clinical outcome of HIV-positive patients. These findings have important implications in the management of melanoma in the setting of HIV disease.
MERKEL CELL CARCINOMA
Merkel cell carcinoma and HIV infection.
Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW.
Lancet 2002 Feb 9;359(9305):497-8 Abstract quote
Merkel cell carcinoma (MCC) is a rare skin cancer that occurs more frequently after organ transplantation or B-cell malignancy, conditions of suppressed or disordered immunity.
To assess further whether immune suppression increases MCC risk, we studied its occurrence in a cohort of 309365 individuals with acquired immunodeficiency syndrome (AIDS) by using linked AIDS and cancer registries.
We identified six cases of MCC, corresponding to a relative risk of 13.4 (95% CI 4.9-29.1) compared with the general population. These results suggest that immune suppression induced by the human immunodeficiency virus increases MCC risk.
PATHOGENESIS CHARACTERIZATION Human immunodeficiency virus
Lentivirus, subgroup retrovirus
This virus mutates frequently and a single patient may develop many mutant strains of the virus
Median time between infection and development of AIDS is 10 years
Currently divided into groups based upon genetic diversity:
Ten subtypes (A-J)
Majority of infected cases
Subtype B is most prevalent strain in US and Western Europe
Group O More severe mechanism attacking 2 additional T cell types Group N Isolated from female patient in Cameroon and may represent a cross between Group M and the simian virus (SIV) Viral infectivity
All determined by the viral titer, viral structure, and the replicating energy and pathogenicity of the virus
Influenced by both the donor and recipient
11 identified genes consisting of 2 identical RNA strands with 2 core proteins, p18 and p24
Spiked envelope surrounding the HIV capsid:
Gp 120 is the envelope glycoprotein, located on the tips of the spikes
Glycoprotein stalk gp41 anchors gp120 to the viral envelope
M-tropic strains target macrophages
T-tropic strains infect T-lymphocytes
HIV infects macrophages at the CD4 site but this infection is dependent upon chemokine coreceptors (CCR5) which determine whether the virus enters the cell or not
First step in the progression of the disease is thought to be binding of the viral gp120 to the CD4 receptor on the T-helper lymphocytes
HIV binding leads to fusion to the host cell membrane with passage, utilizing the fusin protein
Once in the cell, the virus sheds its envelope releasing the viral RNA and the viral enzyme reverse transcriptase which creates a DNA transcript
Viral DNA is transported into the nucleus of the host cell where the viral enzyme integrase integrates the HIV DNA into the host cell's DNA
Once integrated, a DNA polymerase speeds up DNA replication producing large, non-functional polypeptide chains (polyproteins)
Chains are packaged to form immature virions and HIV-1 protease cleaves the polyproteins into smaller, functional proteins, maturing the virion into infectious virions which eventually bud from the cell
Protease enzyme also creates a multitude of viral regulatory and strctural proteins
After seroconversion, most people remain asymptomatic for many years
High rates of viral replication is occurring within the lymph nodes during this period and may be accompanied by a high viral load within the plasma even if the peripheral blood cell viral count is low-this is because only 2% of the total T-cell population is found in the peripheral blood
With depletion of the CD4 T-cells, HIV rises in the peripheral blood and clinical symptoms begin to appear
ANTIGEN PRESENTING CELLS
In Vivo Identification of Langerhans and Related Dendritic Cells Infected with HIV-1 Subtype E in Vaginal Mucosa of Asymptomatic Patients
Lertlakana Bhoopat, M.D., Lukana Eiangleng, M.T., Sungwal Rugpao, M.D., Sarah S. Frankel, M.D., Drew Weissman, M.D., Ph.D., Suree Lekawanvijit, M.D., Supinda Petchjom, M.D., Paul Thorner, M.D., Ph.D. and Tanin Bhoopat, M.D.
Departments of Pathology (LB, LE, SL, SP), Obstetrics and Gynecology (SR), and Forensic Medicine (TB), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Infectious and Parasitic Disease Pathology (SSF), Armed Forces Institute of Pathology, Washington DC; Division of Infectious Diseases (DW), University of Pennsylvania, Philadelphia, Pennsylvania; Division of Pathology (PT), Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology (PT), University of Toronto, Toronto, Canada
Mod Pathol 2001;14:1263-1269 Abstract quote
In Thailand, the predominant HIV subtype is E, rather than Subtype B as in North America and Europe, and the predominant mode of transmission is heterosexual contact. Subtype E has the ability to replicate in vitro in Langerhans cells.
We hypothesized that this cell type might constitute a reservoir for the HIV virus in vaginal mucosa of asymptomatic carriers. To examine this hypothesis, we compared vaginal tissue histology in HIV-1–seropositive cases with seronegative cases and determined the immunophenotype of HIV-1–infected cells, their numbers, and their distribution in vaginal mucosa.
Vaginal biopsies were performed at four different sites from six asymptomatic HIV-1 Subtype E–infected persons and from six seronegative cases at necropsy and examined histologically. Immunophenotyping was performed using immunoperoxidase for Gag p24 HIV, CD3, CD20, CD68, CD1a, S-100 and p55 antigens and by double labeling, combining immunoperoxidase with alkaline phosphatase using pairs of the above antigens.
Twenty of twenty-four vaginal biopsies (83.3%) from HIV-seropositive cases showed definite inflammation compared to five of twenty-four vaginal necropsies (20.8%) from HIV-seronegative cases. One third of HIV-seropositive biopsies (8/24) demonstrated p24-positive cells in the epithelium, whereas three-fourths (18/24) of the biopsies revealed p24-positive cells in the lamina propria. All seropositive patients showed positive cells in at least one biopsy, but not all biopsies contained positive cells. Infected cells were more frequently observed at sites of greater inflammation. The dendritic cell count in HIV-seropositive vaginal epithelium was significantly higher than that observed in the seronegative cases (P = .004). The majority of p24-positive cells in the vaginal epithelium were Langerhans cells (CD1a+/S-100+), whereas in the lamina propria, about half of p24-positive cells were Langerhans-related dendritic cells (p55+ and S-100+) and half were T lymphocytes.
In conclusion, the increased propensity for heterosexual transmission of Subtype E may be related to vaginal inflammation, leading to the accumulation of Langerhans cells and related dendritic cells which, once infected with HIV, can act as a reservoir for further virus transmission.
CKR (CHEMOKINE RECEPTOR GENE)
Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.
Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G, Parmentier M.
IRIBHN and Services de Genetique Medicale, Virologie and Immunodeficiences, Universite Libre de Bruxelles, Belgium.
Nature 1996 Aug 22;382(6593):722-5 Abstract quote
HIV-1 and related viruses require co-receptors, in addition to CD4, to infect target cells. The chemokine receptor CCR-5 (ref.1) was recently demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1 strains, and the orphan receptor LESTR (also called fusin) allows infection by strains adapted for growth in transformed T-cell lines (T-tropic strains).
Here we show that a mutant allele of CCR-5 is present at a high frequency in caucasian populations (allele frequency, 0.092), but is absent in black populations from Western and Central Africa and Japanese populations. A 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains. In a cohort of HIV-1 infected caucasian subjects, no individual homozygous for the mutation was found, and the frequency of heterozygotes was 35% lower than in the general population. White blood cells from an individual homozygous for the null allele were found to be highly resistant to infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major co-receptor for primary HIV-1 strains.
The lower frequency of heterozygotes in seropositive patients may indicate partial resistance.
Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.
Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ.
Laboratory of Genomic Diversity, National Cancer Institute (NCI), Frederick, MD 21702-1201, USA..
Science 1996 Sep 27;273(5283):1856-62 Abstract quote
The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States.
An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS.
Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.
The role of a mutant CCR5 allele in HIV-1 transmission and disease progression.
Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K, Kunstman K, Erickson D, Dragon E, Landau NR, Phair J, Ho DD, Koup RA.
Aaron Diamond AIDS Research Center, New York, New York, USA.
Nat Med 1996 Nov;2(11):1240-3 Abstract quote
A 32-nucleotide deletion (delta 32) within the beta-chemokine receptor 5 (CCR5) gene has been described in subjects who remain uninfected despite extensive exposure to HIV-1. This allele was found to be common in the Caucasian population with a frequency of 0.0808, but was not found in people of African or Asian ancestry.
To determine its role in HIV-1 transmission and disease progression, we analyzed the CCRS genotype of 1252 homosexual men enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS). No infected participant was found to be homozygous for the delta 32 allele, whereas 3.6% of at-risk but uninfected Caucasian participants were homozygous, showing the highly protective role of this genotype against sexual acquisition of HIV-1. No evidence was found to suggest that heterozygotes were protected against HIV-1 infection, but a limited protective role against disease progression was noted.
The delta 32 allele of CCR5 is therefore an important host factor in HIV-1 transmission and pathogenesis.
Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study.
Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, Goedert JJ, O'Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O'Brien SJ.
Science Applications International Corp. Frederick, National Cancer Institute, Frederick, MD 21702-1201, USA.
Science 1997 Aug 15;277(5328):959-65 Abstract quote
The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression.
A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined.
An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.
Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC)
Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, O'Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts E, Vlahov D, Phair J, O'Brien SJ.
Science Applications International Corporation (SAIC), National Cancer Institute, Frederick, MD 21702, USA.
Science 1998 Jan 16;279(5349):389-93 Abstract quote
Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified in an evolutionarily conserved segment of the 3' untranslated region of the SDF-1 structural gene transcript.
In the homozygous state, SDF1-3'A/3'A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies.
The recessive protective effect of SDF1-3'A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.
Mutational analysis of the CCR5 and CXCR4 genes (HIV-1 co-receptors) in resistance to HIV-1 infection and AIDS development among intravenous drug users.
Alvarez V, Lopez-Larrea C, Coto E.
Laboratorio de Genetica Molecular (Instituto Reina Sofia de Investigaciones Nefrologicas), Hospital Central de Asturias, Oviedo, Spain.
Hum Genet 1998 Apr;102(4):483-6 Abstract quote
We analysed a group of Spanish intravenous drug users and controls to determine the role of mutations at the chemokine receptor-5/HIV-1 cofactor (CCR5), previously implicated in resistance to HIV-1 infection, and CXCR4 genes in susceptibility to HIV-1 infection.
The complete coding sequence of both genes was amplified by the polymerase chain reaction from genomic DNA of 50 seropositive slow progressors and 10 long-term non-progressors, and analysed by the single-strand conformation polymorphism technique in a search for mutations. No mutation in CXCR4 was found, and delta ccr5 was the only mutation identified at the CCR5 gene.
We genotyped (delta ccr5 allele) 150 HIV-1+ intravenous drug users and 250 healthy controls from the same population (Asturias, Northern Spain). Patients were divided into rapid progressors, presenting an event indicating progression to the acquired immunodeficiency syndrome (AIDS) in the 2 years after infection (100 patients), and slow progressors, remaining asymptomatic for 2-10 years (50 patients). The frequencies of the delta ccr5 allele were 0.105 and 0.040 in controls and HIV-1+ patients, respectively. Eighteen per cent of the controls (45/250) and 8% (12/150) of the patients carried the delta ccr-5 allele (P=0.013). The frequency of delta ccr5 carriers among rapid and slow disease progressors was 3 and 15%, respectively. A highly significant difference was found between rapid progressors and controls (P=0.0014). No patient (0/150) was delta ccr5 homozygous compared with 1% among controls.
Thus, the delta ccr5 allele (the only CCR5 mutation found in our HIV-1 patients) was rare among seropositive intravenous drug users, suggesting that the absence of this mutation confers an advantage to the virus when infecting cells in vivo. In addition, patients carrying the delta ccr5 allele tend to show a slow progression towards HIV-1-related disease, remaining asymptomatic for longer periods of time.
CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS).
McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, Murphy PM.
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lancet 1998 Sep 12;352(9131):866-70 Abstract quote
BACKGROUND: The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 delta32 and CCR2-641, which alter the protein-coding regions for the HIV-1 coreceptors/chemokine receptors CCR5 and CCR2b. We tested the hypothesis that polymorphisms of the CCR5 promoter might affect the rate of progression of HIV-1 infected people to AIDS.
METHODS: We used directed heteroduplex analysis to identify polymorphism in the CCR5 promoter. Promoter-variants were compared in vitro with a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping HIV-1 seroconvertors discordant at polymorphous loci.
FINDINGS: An A/G polymorphism was identified at basepair 59029 (Genbank U95626) in the CCR5 promoter. Both promoter alleles were common (43-68% allelic frequency for 59029-A depending on race). When in-vitro promoter activity was measured, 59029-G had 45% lower activity than 59029-A (p=0.05). In a cohort of HIV-1 seroconvertors lacking both CCR5 delta32 and CCR2-641, 59029-G/G individuals progressed to AIDS on average 3.8 years more slowly than 59029-A/A individuals (p=0.004). 59029-G/A discordance did not correlate with discordant rates of infection.
INTERPRETATION: Our results are consistent with the hypothesis that CCR5 is important in HIV-1 pathogenesis. CCR5 59029-G/G appears to be protective relative to CCR5 59029-A/A, and about twice as protective relative to CCR5 delta32 or CCR2-641. This effect may be the result of reduced CCR5 mRNA production. These results identify the first site in the CCR5 promoter that may be a useful target for treatment of HIV-1 infection.
Impact of heterozygosity for the chemokine receptor CCR5 32-bp-deleted allele on plasma virus load and CD4 T lymphocytes in perinatally human immunodeficiency virus-infected children at 8 years of age.
Buseyne F, Janvier G, Teglas JP, Ivanoff S, Burgard M, Bui E, Mayaux MJ, Blanche S, Rouzioux C, Riviere Y.
Unite de Virologie et Immunologie Cellulaire, Institut Pasteur, Paris, France.
J Infect Dis 1998 Oct;178(4):1019-23 Abstract quote
The CCR5 gene encodes one of the major human immunodeficiency virus type 1 (HIV-1) coreceptors. A 32-bp deletion in this gene (delta ccr5) is associated with relative resistance to disease progression in heterozygous HIV-1-infected persons.
The effect of this mutation on virologic and immunologic parameters was determined in a cohort of 45 perinatally HIV-1-infected children prospectively followed after 5 years of age. At a median age of 8.3 years, heterozygous children had significantly lower virus load than homozygous children (median, 3.3 vs. 4.1 log copies/mL, P < .009) and higher percentages of CD4 T cells (median, 26% vs. 17%, P < .07). However, there was no discernible influence of the CCR5 genotype on the percentages of CD8 T cells (P < .27) or on HIV-specific cytotoxic T lymphocyte activities (P < .65). There was a trend for lower rates of progression to AIDS (CDC stage C) in heterozygous children.
These data confirm a major role for the CCR5 coreceptor in HIV-1 pathogenesis in children.
A 32-bp deletion within the CCR5 locus protects against transmission of parenterally acquired human immunodeficiency virus but does not affect progression to AIDS-defining illness.
Wilkinson DA, Operskalski EA, Busch MP, Mosley JW, Koup RA.
Department of Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9113, USA.
J Infect Dis 1998 Oct;178(4):1163-6 Abstract quote
The beta-chemokine receptor CCR5 is required as a coreceptor by non-syncytium-inducing (NSI) strains of human immunodeficiency virus type 1 (HIV-1). NSI viruses predominate early during an infection and are thought to be important for the transmission of HIV-1. The importance of CCR5 during parenteral transmission of HIV-1 was investigated.
The distribution of the homozygous deleted CCR5 genotype among 566 exposed persons with hemophilia and 97 exposed transfusion recipients indicated that the lack of CCR5 expression protected persons from infection. This suggests that the initial predominance of NSI viruses during an infection does not result from limited availability of CXCR4-expressing cells within the mucosa but rather implies a more fundamental requisite for CCR5-expressing cells early during an infection regardless of the route of transmission.
In addition, no difference in the rate of progression to AIDS (CDC 1987 definition) of infected heterozygous compared with homozygous wild type subjects was observed.
Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms in AIDS progression.
Hendel H, Henon N, Lebuanec H, Lachgar A, Poncelet H, Caillat-Zucman S, Winkler CA, Smith MW, Kenefic L, O'Brien S, Lu W, Andrieu JM, Zagury D, Schachter F, Rappaport J, Zagury JF.
Laboratoire de Physiologie Cellulaire, Universite Pierre et Marie Curie, Paris, France.
J Acquir Immune Defic Syndr Hum Retrovirol 1998 Dec 1;19(4):381-6 Abstract quote
The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients.
Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = . 12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (64I) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes.
Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is >8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects.
Genetic acceleration of AIDS progression by a promoter variant of CCR5.
Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, Michael NL, Lee B, Doms RW, Margolick J, Buchbinder S, Goedert JJ, O'Brien TR, Hilgartner MW, Vlahov D, O'Brien SJ, Carrington M.
Science Applications International Corporation (SAIC), National Cancer Institute, Frederick MD 21702, USA.
Science 1998 Dec 4;282(5395):1907-11 Abstract quote
The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1).
Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype.
The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.
Combined genotypes of CCR5, CCR2, SDF1, and HLA genes can predict the long-term nonprogressor status in human immunodeficiency virus-1-infected individuals.
Magierowska M, Theodorou I, Debre P, Sanson F, Autran B, Riviere Y, Charron D, Costagliola D.
Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR CNRS 7627, Hopital Pitie-Salpetriere, Paris, France.
Blood 1999 Feb 1;93(3):936-41 Abstract quote
Human immunodeficiency virus (HIV)-1-infected long-term nonprogressors (LT-NP) represent less than 5% of HIV-1-infected patients.
In this work, we tried to understand whether combined genotypes of CCR5-triangle up32, CCR2-64I, SDF1-3'A and HLA alleles can predict the LT-NP status. Among the chemokine receptor genotypes, only the frequency of the CCR5-triangle up32 allele was significantly higher in LT-NP compared with the group of standard progressors. The predominant HLA alleles in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7. A combination of both HLA and chemokine receptor genotypes integrated in a multivariate logistic regression model showed that if a subject is heterozygous for CCR5-triangle up32 and homozygous for SDF1 wild type, his odds of being LT-NP are increased by 16-fold, by 47-fold when a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also if at least three of the following alleles are present: HLA-A3, HLA-B14, HLA-B17, HLA-DR7. This model allowed a correct classification of 70% of LT-NPs and 81% of progressors, suggesting that the host's genetic background plays an important role in the evolution of HIV-1.
The chemokine receptor and chemokine genes along with the HLA genotype can serve as predictors of HIV-1 outcome for classification of HIV-1-infected subjects as LT-NPs or progressors.
Persistent CCR5 utilization and enhanced macrophage tropism by primary blood human immunodeficiency virus type 1 isolates from advanced stages of disease and comparison to tissue-derived isolates.
Li S, Juarez J, Alali M, Dwyer D, Collman R, Cunningham A, Naif HM.
Centre for Virus Research, Westmead Millennium Institute, National Centre for HIV Virology Research, Westmead, NSW 2145, Australia.
J Virol 1999 Dec;73(12):9741-55 Abstract quote
Viral phenotype, tropism, coreceptor usage, and envelope gene diversity were examined in blood isolates collected from 27 individuals at different stages of human immunodeficiency virus type 1 (HIV-1) disease and tissue derived isolates from 10 individuals with AIDS.
The majority (89%) of blood and all tissue HIV-1 isolates from all stages of infection were non-syncytium inducing and macrophage (M) tropic. Tropism and productive infection by HIV isolates in both monocytes and monocyte-derived macrophages (MDM) increased in advanced disease (HIV tropism for monocytes, 1 of 6 from categories I and II versus 11 of 21 [P = 0.05] from category IV and II [CD4 < 250]; and high-level replication in MDM, 1 of 6 from categories I and II versus 16 of 21 from categories IV and II [P = 0. 015]). There was a high level of replication of blood and tissue isolates in T lymphocytes without restriction at any stage.
Overall, the level of replication in MDM was 5- to 10-fold greater than in monocytes, with restriction in the latter occurring mainly at entry and later stages of replication. Only three blood isolates were identified as syncytium inducing, and all had a dualtropic phenotype. There was a significant increase of HIV envelope gene diversity, as shown by a heteroduplex mobility assay, in advanced disease; this may partly underlie the increase of HIV replication in MDM. Unlike blood isolates (even those from patients with advanced disease), tissue isolates displayed greater similarities (90%) in productive infection between MDM and monocytes. The majority (87%) of all isolates, including those from patients with advanced disease, used CCR5, and only 5 of 37 isolates showed expanded coreceptor usage.
These results indicate that in the late stage of disease with increasing viral load and diversity, CCR5 utilization and M-tropism persist in blood and tissue and the replicative ability in macrophages increases. This suggests that these characteristics are advantageous to HIV and are important to disease progression.
The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV disease progression in individuals with haemophilia.
Pasi KJ, Sabin CA, Jenkins PV, Devereux HL, Ononye C, Lee CA.
Department of Haematology, Katharine Dormandy Haemophilia Centre, Royal Free and University College Medical School, London, UK.
Br J Haematol 2000 Oct;111(1):136-42 Abstract quote
The chemokine receptor CCR5 is an important co-receptor for cell fusion. A 32-bp deletion of the CCR5 gene, leading to complete absence of functional CCR5 expression, has been associated with resistance to human immunodeficiency virus (HIV) infection in homozygotes and slower HIV disease progression in heterozygotes.
The objectives of this study were to assess the effects of this 32-bp deletion on transmission of HIV infection and on HIV disease progression in haemophilic individuals. Six HIV-negative patients from our centre, known to have been exposed to infectious factor VIII concentrates, have been analysed. Three of these patients possess the CCR5 32-bp deletion, two patients being homozygous. The presence of the CCR5 32-bp gene deletion has also been analysed in 71 HIV-positive patients. In this group of patients, there was a lower than expected incidence of the 32-bp deletion. Those who possess the 32-bp deletion progress to AIDS more slowly than those who do not (P = 0.05, log-rank test). Rates of CD4 loss were slower in those heterozygous for the gene deletion.
We confirm that heterozygosity for the 32-bp gene deletion in CCR5 is partially protective against initial infection with HIV. In those heterozygous patients who became infected with HIV, disease progression was slower.
HIV-specific cytotoxic T lymphocytes, HLA-A11, and chemokine-related factors may act synergistically to determine HIV resistance in CCR5 delta32-negative female sex workers in Chiang Rai, northern Thailand.
Sriwanthana B, Hodge T, Mastro TD, Dezzutti CS, Bond K, Stephens HA, Kostrikis LG, Limpakarnjanarat K, Young NL, Qari SH, Lal RB, Chandanayingyong D, McNicholl JM.
Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000 Thailand.
AIDS Res Hum Retroviruses 2001 May 20;17(8):719-34 Abstract quote
Understanding how highly HIV-exposed individuals remain HIV uninfected may be useful for HIV vaccine design and development of new HIV prevention strategies.
To elucidate mechanisms associated with resistance to HIV infection, immunologic and genetic factors were examined in 14 HIV-exposed but persistently seronegative (HEPS) female sex workers from Chiang Rai, northern Thailand and in ethnically matched, HIV-positive (n = 9) and HIV-negative women (n = 9). The HEPS women were identified in a study of commercial sex workers who had an HIV-1 incidence of 20.3 per 100 person-years. A high frequency of HLA-A11 was observed in HEPS women (86%) compared with northern Thai controls (56%). HIV-specific cytotoxic T lymphocyte (CTL) lytic responses were detected in cryopreserved peripheral blood mononuclear cells (PBMCs), using HLA-A-matched subtype E HIV-1 peptides in four of seven (57%) HEPS women, eight of eight HIV-positive women, and zero of nine HIV-negative unexposed controls (p = 0.019 HEPS women vs. HIV-negative controls). CTL lysis levels were low, but responses were detected to peptides from Nef, Pol, Gag, and Env. Nef responses predominated in HEPS women.
Compared with controls, HEPS women tended to have higher frequencies of CCR5 promotor 59402GG and SDF-1 3'UTR 801A genotypes known to influence HIV transmission or course of disease. HEPS women also had higher levels of spontaneous RANTES production by PBMCs than other groups. Each of these factors could potentially contribute to HIV resistance. As most HEPS women had one or more of these factors, they may prevent HIV infection synergistically by blocking HIV cell entry, delaying its dissemination, or killing HIV-infected cells.
Polymorphism of CCR5 affecting HIV disease progression in the Japanese population.
Kageyama S, Mimaya J, Yamada K, Kurimura T, Shiraki K; Research Committee on Prevention of Developing Illness and Therapy for HIV-infected People.
Department of Virology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
AIDS Res Hum Retroviruses 2001 Jul 20;17(11):991-5 Abstract quote
Among several factors associated with HIV-1 disease progression, genetic polymorphism of CCR2, CCR5, and CXCR4 in HIV-1 infection has been found. Single-nucleotide polymorphisms (SNPs) in the CCR2, CCR5, and CXCR4 genes as well as a 32-base pair deletion in the open reading frame of the CCR5 gene are associated with HIV disease progression among Caucasians and African-Americans in North America and Europe. However, in populations other than Caucasians and African-Americans, SNPs have not been fully examined.
In our study SNPs in CCR2 coding and CCR5 regulatory regions have been examined in 98 Japanese HIV-positive individuals. The alleles of CCR5 regulatory regions at -2135T and -2086G are associated with late onset of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 0.502 and 0.404, respectively). In contrast to this, the allele of CCR5 at -2086A is associated with the early onset of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 2.133). A haplotype including two alleles at -2135G and -2086G is associated with the late onset of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 0.372). Thus we found that a CCR5 SNP and haplotype polymorphism affect HIV disease progression even in the Japanese population.
This indicates that the CCR5 genetic polymorphism affecting disease progression should be studied in a wider range of population.
Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.
Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL, Buchbinder SP, Coutinho RA, Eugen-Olsen J, Gallart T, Katzenstein TL, Kostrikis LG, Kuipers H, Louie LG, Mallal SA, Margolick JB, Martinez OP, Meyer L, Michael NL, Operskalski E, Pantaleo G, Rizzardi GP, Schuitemaker H, Sheppard HW, Stewart GJ, Theodorou ID, Ullum H, Vicenzi E, Vlahov D, Wilkinson D, Workman C, Zagury JF, O'Brien TR; International Meta-Analysis of HIV Host Genetics.
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
Ann Intern Med 2001 Nov 6;135(9):782-95 Abstract quote
BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results.
OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression.
DESIGN: Meta-analysis of individual-patient data.
SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia.
PATIENTS: Patients with HIV-1 infection who were of European or African descent.
MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models.
RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all).
CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.
Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines.
Bannert N, Craig S, Farzan M, Sogah D, Santo NV, Choe H, Sodroski J.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Exp Med 2001 Dec 3;194(11):1661-73 Abstract quote
The chemokine receptor CCR5 plays an important role in leukocyte chemotaxis and activation, and also acts as a coreceptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV).
We provide evidence that CCR5 is O-glycosylated on serine 6 in the NH2 terminus. The O-linked glycans, particularly sialic acid moieties, significantly contribute to binding of the chemokine ligands. By contrast, removal of O-linked oligosaccharide exerted little effect on HIV-1 infection. Sulfation of specific tyrosine residues in the CCR5 NH2 terminus was important for efficient beta-chemokine binding. Thus, as has been observed for the binding of selectins and their ligands, O-linked carbohydrates and tyrosine sulfates play major roles in promoting the interaction of chemokines with CCR5. The resulting flexible arrays of negative charges on the CCR5 surface may allow specific, high-affinity interactions with diverse chemokine ligands.
Although this is the first example of O-linked oligosaccharides and tyrosine sulfates playing a role in chemokine binding, the high density of serines, threonines and tyrosines in the N-termini of many CC chemokine receptors suggests that these posttranslational modifications may commonly contribute to chemokine binding.
Chemokine-mediated block to HIV entry is associated with CCR5 internalization efficiency.
Brandt SM, Mariani R, Holland AU, Hope TJ, Landau NR.
Infectious Disease Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
J Biol Chem 2002 Jan 8 Abstract quote
Chemokines inhibit entry of HIV into CD4+ T cells more effectively than into macrophages or transfected adherent cells. Here, we tested whether chemokine receptor internalization could account for cell-type differences in the effectiveness of chemokines. Infection of CEM T cells expressing stably transduced wild-type CCR5 was much more readily inhibited by chemokine than were transduced HOS cells.
This response correlated with the efficiency of CCR5 internalization. A mutated CCR5, termed M7-CCR5, in which the potential Ser/Thr phosphorylation sites in the cytoplasmic tail were changed to Ala did not internalize in response to MIP-1a. M7-CCR5 was expressed at slightly higher levels than wild-type on stably transduced cell lines and was somewhat more potent as an HIV-1 coreceptor. The mutated receptor mobilized intracellular Ca2+ in response to chemokine to a level four-fold higher than did the wild type CCR5. Unexpectedly, the receptor was desensitized as efficiently as wild-type, suggesting that desensitization does not require cytoplasmic tail phosphorylation. Entry of R5 HIV-1 reporter virus into cells stably expressing M7-CCR5 was largely resistant to blocking by MIP-1a. As much as 80% of entry inhibition was attributed to receptor internalization. AOP-MIP-1a was able to induce a low level of M7-CCR5 internalization in HOS and to weakly inhibit HIV-1 entry. Introduction of dominant-negative dynamin into HOS cells reduced the ability of chemokine to inhibit infection.
The inefficiency of internalization of chemokine receptors in some cell-types could allow virus to replicate in vivo in the presence of endogenous chemokine. Lastly, M7-CCR5 may be a useful tool for discriminating coreceptor internalization from binding site masking mechanisms in the evaluation of small molecule inhibitors of HIV-1 entry.
Analysis of CCR5Delta32 Geographic Distribution and Its Correlation with Some Climatic and Geographic Factors.
Limborska SA, Balanovsky OP, Balanovskaya EV, Slominsky PA, Schadrina MI, Livshits LA, Kravchenko SA, Pampuha VM, Khusnutdinova EK, Spitsyn VA.
Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.
Hum Hered 2002;53(1):49-54 Abstract quote
We studied the possible effects of climatic-geographic factors on the world distribution of the mutant allele for the chemokine receptor gene CCR5, which has a 32-bp deletion (CCR5Delta32) preventing cell invasion by the primary transmitting strain of HIV-1. New data on CCR5 polymorphisms in Russian, Ukrainian, and Moldavian populations are presented. All available data on CCR5Delta32 frequencies in the Old World (number of populations n = 77) were used for construction of a geographical gene map to analyze possible correlations between allele frequencies and eight climatic-geographic parameters.
A strong positive correlation was found between the allele frequency and latitude (r = 0.72), a strong negative correlation with annual radiation balance (r = -0.66), and a weaker negative correlation with longitude (r = -0.34). Partial correlations were calculated excluding the influence of latitude. The negative correlation between the allele frequency and annual radiation balance decreased (r = -0.42), but remained large and significant.
We propose that the existence of correlations between the cline of CCR5Delta32 frequencies and climatic-geographic parameters provides evidence for a possible effect of either natural environmental factors or large-scale population movements on the distribution of this allele.
Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1.
Faure S, Meyer L, Costagliola D, Vaneensberghe C, Genin E, Autran B, Delfraissy JF, McDermott DH, Murphy PM, Debre P, Theodorou I, Combadiere C.
Laboratoire d'Immunologie Cellulaire et Tissulaire, Centre National de la Recherche Scientifique UMR 7627, Hopital Pitie-Salpetriere, Paris, France.
Science 2000 Mar 24;287(5461):2274-7 Abstract quote
Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor.
Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5. Here two single nucleotide polymorphisms are described in Caucasians in CX3CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes.
Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX3CR1-I249 M280 is a recessive genetic risk factor in HIV/AIDS
The role of cytokines in the pathogenesis and management of AIDS-related lymphomas.
Fassone L, Gaidano G, Ariatti C, Vivenza D, Capello D, Gloghini A, Cilia AM, Buonaiuto D, Rossi D, Pastore C, Carbone A, Saglio G.
Department of Medical Sciences, Amedec Avogadro University of Eastern Piedmont, Novara, Italy.
Leuk Lymphoma 2000 Aug;38(5-6):481-8 Abstract quote
AIDS-related non-Hodgkin lymphomas (AIDS-NHL) consistently derive from B-cells and are characterized by extreme clinical aggressiveness. At histological level, AIDS-NHL are classified as AIDS-related Burkitt's lymphoma (AIDS-BL), AIDS-related diffuse large cell lymphoma (AIDS-DLCL) and AIDS-related primary effusion lymphoma (AIDS-PEL). The role of cytokines in the pathogenesis and management of AIDS-NHL has been studied to a certain extent.
Production of large quantities of human IL-10 occurs frequently in AIDS-BL and correlates with latent EBV infection of the tumor clone. Lesser amounts of the cytokine are released in EBV negative cases. The pathogenetic role of IL-10 in AIDS-BL is suggested by the observation that IL-10 antisense oligonucleotides inhibit proliferation of the lymphoma. A significant fraction of AIDS-BL cell lines produce TNFbeta. Among AIDS-NHL, the release of TNFbeta appears to be specific for AIDS-BL. The pathogenetic relevance of TNFbeta in lymphomagenesis is suggested by the observation that some BL cell lines use TNFbeta as an autocrine growth factor. Some cases of AIDS-BL, particularly those carrying EBV infection, also secrete IL-6, IL-7 and IL-12. With respect to AIDS-DLCL, many cases express the IL-6R, rendering these cells responsive to the paracrine stimulation by the IL-6 produced by nearby T-cells, macrophages and endothelial cells which are frequently abundant in these tumor samples. The tumor clone itself, however, generally fails to release IL-6. AIDS-PEL is characterized by secretion of large amounts of IL-6 and IL-10. Some PEL cases also release oncostatin M. Apart from human IL-6, PEL also express viral IL-6, which is encoded by the HHV-8 genome. The biological relevance of both IL-6 and IL-10 in PEL proliferation and growth has been recently clarified in vitro and in vivo.
Overall, these data suggest that activation of different cytokine loops clusters with different clinico-pathologic categories of AIDS-NHL and may represent the potential target of novel therapeutic strategies.
Regulation of Fas Expression in the Lymph Nodes of Patients Infected With Human Immunodeficiency Virus
Liqiang Wang, MD, PhD and Patrick A. Adegboyega, MD
From the Department of Pathology, The University of Texas Medical Branch, Galveston, Tex.
Arch Pathol Lab Med 2002;126, No. 1, pp. 28–32. Abstract quote
Context.—The mechanism by which human immunodeficiency virus 1 (HIV-1) infection causes increased rates of apoptosis and gradual chronic depletion of CD4+ T lymphocytes in patients infected with HIV-1 is not known. Findings from in vitro culture studies and analysis of mononuclear cells in the peripheral blood of HIV-infected patients have led to the hypothesis that abnormal expression and/or interaction of Fas and Fas ligand (FasL) may play significant roles in the derangement of homeostasis of CD4+ lymphocytes in patients infected with HIV-1.
Objective.—To determine the in situ expression of Fas and FasL in the lymph nodes of patients infected with HIV-1. Design.—Immunohistochemical expression of Fas and FasL was studied in the lymph node biopsy specimens from 20 patients infected with HIV-1. As controls, we also studied 120 lymph nodes from 28 HIV-1–seronegative patients with reactive lymphadenopathy.
Results.—In the reactive lymph nodes of seronegative patients, expression of Fas was diffuse in the germinal centers and also in immunoblast-like cells in the T-cell regions. In the lymph nodes of patients infected with HIV, there was a consistent remarkable decrease in Fas expression in 12 of 20 patients and a total lack of Fas expression in the remaining 8 patients. Expression of FasL was comparable in both patient groups.
Conclusions.—There is marked down-regulation of Fas in the lymph nodes of HIV-infected patients, a sharp contrast to what occurs in circulating mononuclear cells in the peripheral blood of these patients. These results indicate the need for further studies of this molecular event for possible therapeutic intervention based on reconstitution of Fas and/or FasL activity in the treatment of HIV infection.
IMMUNOSUPPRESSION HIV-1 and causal relationship to immunosuppression and nervous system disease in AIDS Hum Pathol 2000;31:1274-1298
Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR: Consequences for HIV infection and immunity.
Soilleux EJ, Morris LS, Rushbrook S, Lee B, Coleman N.
Medical Research Council Cancer Centre Unit, Hutchison/MRC Research Centre, Cambridge, UK; Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, UK; and Department of Microbiology, Immunology & Molecular Genetics, UCLA, Los Angeles, CA.
Hum Pathol 2002 Jun;33(6):652-9 Abstract quote
DC-SIGNR is a human immunodeficiency virus (HIV)-binding C-type lectin that is expressed on endothelium in the hepatic sinusoids, lymph node sinuses and placenta. Like closely related DC-SIGN, DC-SIGNR can bind both ICAM-3 and HIV and can potentiate HIV infection of T lymphocytes in trans.
In the present study we have investigated reasons underlying the restricted distribution of DC-SIGNR and have examined DC-SIGNR expression in relation to HIV entry receptors. We show that DC-SIGNR expression does not depend on endothelial cell specialization or on activation state. DC-SIGNR-positive endothelium continues to express DC-SIGNR in conditions of hyperplasia, whereas the molecule is lost after neoplastic transformation, most likely as a result of changes in the microenvironment of the endothelial cells.
We have further shown that CCR5, but not CD4, is coexpressed with DC-SIGNR on hepatic sinusoidal and placental capillary endothelial cells. However, CD4-positive CCR5-positive cells, such as hepatic Kupffer cells, placental Hofbauer cells, and CD4-positive T lymphocytes in lymph nodes, can be found adjacent to DC-SIGNR-positive endothelium. Therefore, DC-SIGNR may be able to mediate HIV infection of these cells in trans. Finally, we demonstrate that DC-SIGN and DC-SIGNR can be coexpressed on lymph node sinus endothelial cells, which may lead to modulation of the function of both molecules.
RB2/p130 TUMOR SUPPRESSOR GENE
Expression of RB2/p130 tumor-suppressor gene in AIDS-related non-Hodgkin's lymphomas: implications for disease pathogenesis.
Lazzi S, Bellan C, De Falco G, Cinti C, Ferrari F, Nyongo A, Claudio PP, Tosi GM, Vatti R, Gloghini A, Carbone A, Giordano A, Leoncini L, Tosi P.
Institute of Pathological Anatomy and Histology, University of Siena, Siena, Italy.
Hum Pathol 2002 Jul;33(7):723-31 Abstract quote
In this study we examined 21 cases of AIDS-related lymphomas for genomic organization and expression of RB2/p130 oncosuppressor gene and compared the results with the proliferative features of these neoplasms.
We found no mutations in the RB2/p130 gene and unusually high percentages of cells expressing nuclear pRb2/p130 in tumors with a high proliferative activity, such as AIDS-related lymphomas. These findings might suggest that a molecular mechanism usually observed in viral-linked oncogenesis could be involved. We performed in vitro and in vivo binding assays to investigate whether the human immunodeficiency virus (HIV) gene product Tat and Rb2/p130 could interact. The results of these assays revealed that the HIV-1 Tat protein binds specifically to pRb2/p130. This may result in the inactivation of its oncosuppressive properties and the induction of genes needed to proceed through the cell cycle including p107, cyclin A, and cyclin B.
Using single-cell polymerase chain reaction (PCR) assay, we found HIV-1 DNA in the neoplastic cells of only 2 of the 21 cases examined, whereas PCR on whole tissue revealed HIV-1 DNA in all of the cases. Furthermore, a diffuse and nuclear stain was observed in tissue sections with anti-Tat monoclonal antibody. These findings are in accordance with the notion that soluble Tat protein could function as a biologically active extracellular protein released by infected cells and taken up readily by uninfected B cells. In conclusion, our results seem to suggest that pRb2/p130 oncosuppressor protein may be a target in the interaction between the HIV-1 gene products and host proteins.
CHARACTERIZATION Laboratory Markers Screening EIA test
Must be repeatedly reactive
If patient has repeatedly reactive tests but negative confirmatory test, considered uninfected unless viral culture, PCR, and p24 antigen testing is positive
May not detect antibodies until one to two months after infection
Confirmation Test Western Blot or IFA test Disease progression Viral load Measures viral RNA in plasma but does not measure viral load in the lymph or other tissues Branched DNA (bDNA) Directly quantify viral RNA at physiologic levels and highly accurate ANA/ANCA/BASEMENT MEMBRANE ANTIBODIES
Anti-nuclear, anti-neutrophil cytoplasmic and anti-glomerular basement membrane antibodies in HIV-infected individuals.
Savige JA, Chang L, Horn S, Crowe SM.
University Department of Medicine, Austin Hospital, Heidelberg, Victoria, Australia.
Autoimmunity 1994;18(3):205-11 Abstract quote
Many autoantibodies have been described in HIV-infected individuals.
We have examined the incidence, associations and prognostic significance of anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement membrane (GBM) antibodies in individuals with HIV infections.
One hundred and five patients, with asymptomatic infections (n = 37), AIDS-related complex (n = 32) or AIDS (n = 36) were studied.
Plasma from 24 of these (23%) were positive for ANA: most demonstrated speckled fluorescence (n = 21) and were of low titre (1+ in 18). ANCA were demonstrated by IIF in 18 individuals (17%) and all fluorescent patterns were seen; 6 of these plasma were also positive in the ELISAs for antibodies to proteinase 3, myeloperoxidase or elastase. Thirteen plasma were positive for ANCA in the neutrophil cytoplasm ELISA; 10 of these were also positive in the specific ELISAs. A total of 30 plasma bound to proteinase 3, myeloperoxidase or elastase in specific ELISAs, in 6 cases with 2 specificities. Finally, 18 plasma (17%) contained anti-GBM antibodies by ELISA, but none of 4 plasma tested in inhibition assays was specific.
ANA, ANCA and anti-GBM antibodies were not uncommon in HIV-infected individuals but the presence of these antibodies was not associated with the clinical manifestations of the corresponding autoimmune diseases. In addition, there was no correlation between the demonstration of these antibodies and the immunological status of the individual (apart from a correlation between CD4 counts less than 400/microliters with anti-GBM antibodies), the presence of an opportunistic infection, the development of malignancy or reduced survival. Some of these antibodies may arise from polyclonal activation, or be due to "sticky" serum since we have shown that the presence of anti-GBM antibodies correlated with the demonstration of ANCA by ELISA. These antibodies are not more common in hypergammaglobulinemic plasma but some may be due to heat-treatment of the plasma.
The clinician caring for HIV-infected individuals needs to be aware of these "false-positive" antibody results.
Impact of HIV Infection and HAART on Serum Lipids in Men.
Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella F, Visscher B, Evans R, Kingsley LA.
University of Pittsburgh, Pittsburgh, Pa.
JAMA. 2003 Jun 11;289(22):2978-82. Abstract quote
CONTEXT: Alterations in serum lipid values have been widely reported among persons infected with human immunodeficiency virus (HIV) type 1 treated with highly active antiretroviral therapy (HAART), but no data have yet been reported on changes from preseroconversion lipid values.
OBJECTIVE: To describe changes in serum cholesterol levels associated with HIV infection and antiretroviral medication exposure, and 1-time assessment of triglyceride levels post-HAART initiation.
DESIGN, SETTING, AND PARTICIPANTS: The Multicenter AIDS Cohort Study, a prospective study in which homosexual and bisexual men were enrolled and from which 50 of 517 HIV seroconverters were drawn for the analysis herein, who later initiated HAART, involving measurements of stored serum samples obtained between 1984 and 2002.
MAIN OUTCOME MEASURES: Changes in levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at 6 time points during an average of 12 years; 1-time assessment of triglyceride levels from the third post-HAART clinic visit. RESULTS: Among the 50 men, notable declines in mean serum TC (-30 mg/dL [-0.78 mmol/L]), HDL-C (-12 mg/dL [-0.31 mmol/L]), and LDL-C values (-22 mg/dL [-0.57 mmol/L]) were observed after HIV infection. Following HAART initiation, there were large increases in mean TC and LDL-C values (50 and 21 mg/dL [1.30 and 0.54 mmol/L], respectively); however, the mean changes from the preseroconversion values were 20 mg/dL (0.52 mmol/L) (95% confidence interval [CI], -1 to 41) and -1 mg/dL (-0.03 mmol/L) (95% CI, -25 to 22), respectively. Mean HDL-C remained below baseline levels throughout follow-up. The median value (interquartile range) of triglycerides was 225 mg/dL (2.54 mmol/L) (147-331 mg/dL).
CONCLUSIONS: Before treatment, HIV infection results in substantial decreases in serum TC, HDL-C, and LDL-C levels. Subsequent HAART initiation is associated with increases in TC and LDL-C but little change in HDL-C. Increases in TC and LDL-C observed after about 3 years of HAART possibly represent a return to preinfection serum lipid levels after accounting for expected age-related changes.
VIRAL LOAD RNA Lowering the Detection Limits of HIV-1 Viral Load Using Real-Time Immuno-PCR for HIV-1 p24 Antigen
Janet M. Barletta, PhD, Daniel C. Edelman, MS, and Niel T. Constantine, PhD
Am J Clin Pathol 2004;122:20-27 Abstract quote
Presently, the assay that attains maximal sensitivity and dynamic range of HIV-1 viral copy number (50 copies per milliliter) is nucleic acid amplification of HIV RNA in plasma. Enzyme-linked immunosorbent assay (ELISA) methods for quantification of HIV-1 p24 antigen have been relatively insensitive.
In this report, we show data that indicate real-time immuno–polymerase chain reaction (IPCR), a combination of the ELISA and PCR techniques, is more sensitive for HIV-1 p24 antigen detection than other currently reported methods. When derived from an IPCR standard curve, a dose response was observed from patient samples with known viral loads diluted within a 3-log range (1.68-6,514 viral RNA copies per milliliter). IPCR detected 42% (22/52) of patient samples that had fewer than 50 viral RNA copies per milliliter by reverse transcriptase–PCR.
IPCR shows the potential to become the most analytically sensitive test available for determination of HIV-1 viral load by the detection of HIV-1 p24 antigen.
A Modified Ultrasensitive Assay to Detect Quantified HIV-1 RNA of Fewer Than 50 Copies per Milliliter
Estelle M. Piwowar-Manning, MT, SI,1 Terry A. Henderson, MT,1 Lorraine Brisbin, MS,2 and J. Brooks Jackson, MD, MBA
Am J Clin Pathol 2003;120:268-270 Abstract quote
We compared the sensitivity and specificity of versions 1.0 and 1.5 and a modified version 1.5 of the AMPLICOR HIV-1 MONITOR ultrasensitive RNA assay (Roche, Indianapolis, IN) by using a virus stock dilution series and plasma samples from HIV-1– infected and uninfected subjects.
The modified assay was linear and consistently positive down to 12 copies per milliliter vs 25 copies per milliliter for the other 2 assays. Versions 1.0, 1.5, and modified 1.5, respectively, detected 9 (23%) of 39, 11 (28%) of 40, and 43 (61%) of 71 replicates of a 4-copy-number and 11 (28%) of 40, 17 (46%) of 37, and 88 (90%) of 98 replicates of a 10-copy-number standard. Of 44 patient samples with undetectable levels using version 1.0, 32 (73%) had detectable levels on the modified assay, and 5 (25%) of 20 had detectable levels on version 1.5.
None of the assays detected HIV-1 RNA in HIV-1 antibody–negative samples. The modified version 1.5 of the RNA assay is more sensitive for detecting HIV-1 RNA in significantly more patients than are versions 1.0 and 1.5.
Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study.
O'Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen AR, Luban N, Hatzakis A, Aledort LM, Rosenberg PS, Miley WJ, Kroner BL, Goedert JJ.
Viral Epidemiology Branch, National Cancer Institute, Rockville, MD 20852, USA.
JAMA 1996 Jul 10;276(2):105-10 Abstract quote
OBJECTIVE--To determine if the long-term incidence of the acquired immunodeficiency syndrome (AIDS) is related to human immunodeficiency virus type 1 (HIV-1) RNA levels measured early in HIV-1 infection.
DESIGN--Epidemiologic cohort study.
SETTING--Five hemophilia treatment centers in the United States.
SUBJECTS--A total of 165 subjects with hemophilia and HIV-1 infection (age at HIV-1 seroconversion, 1-66 years) followed from 1979 to 1995.
METHODS--The HIV-1 RNA level was measured by polymerase chain reaction over a range of 200 to 1 million or more HIV-1 RNA copies/mL in archived serum specimens collected 12 to 36 months (median, 27 months) after the estimated date of HIV-1 seroconversion. Kaplan-Meier methods were used to examine the risk of AIDS and proportional hazards models were used to estimate relative hazards.
RESULTS--The HIV-1 RNA values were similar in subjects younger than 17 years at seroconversion (median, 5214 copies/mL) and those 18 to 34 years old (median, 4693 copies/mL), but higher in those 35 years or older (median, 12069 copies/mL) (P = .02 compared with each younger group). At 10 years after seroconversion, the proportions of subjects with AIDS were 72% among subjects with 100,000 or more HIV-1 RNA copies/mL measured 12 to 36 months after HIV-1 seroconversion (n = 9), 52% among subjects with 10,000 to 99,999 copies/mL (n = 55), 22% among subjects with 1000 to 9,999 copies/mL (n = 82), and 0% among subjects with fewer than 1000 copies/mL (n = 19) (P < .001). The age-adjusted relative hazard for AIDS for subjects with 10,000 or more copies/mL was 14.3 (95% confidence interval, 1.9-105.6) compared with subjects with fewer than 1000 copies/mL.
CONCLUSIONS--The HIV-1 RNA level during early chronic HIV-1 infection is a strong, age-independent predictor of clinical outcome; low levels define persons with a high probability of long-term AIDS-free survival.
Effects of plasma HIV RNA, CD4+ T lymphocytes, and the chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. Hemophilia Growth and Development Study.
Daar ES, Lynn H, Donfield S, Gomperts E, Hilgartner MW, Hoots K, Chernoff D, Winkler C, O'Brien SJ.
Cedars-Sinai Burns & Allen Research Institute, Department of Medicine, and the University of California Los Angeles School of Medicine, 90048, USA.
J Acquir Immune Defic Syndr 1999 Aug 1;21(4):317-25 Abstract quote
We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs.
We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genoytpe variants CCR2b-641 and CCR5-delta32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4+ T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4+ T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059).
We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte number
CHARACTERIZATION General General constitutional symptoms of malaise, nausea, vomiting, diarrhea, chills, fever, night sweats, myalgias and arthralgias, lethargy, fatigue Exposure and Infection
Acute infection is accompanied with general constitutional symptoms
Usually 2 weeks to 6 months after infection
CD4 count 800-1200
6 months to 11+ years
CD4 count >500
Chronic asymptomatic state HIV infected, long term non progressors
Ultimate progression unknown
CD4 count <200
Epidemiology and microbiology of cellulitis and bacterial soft tissue infection during HIV disease: a 10-year survey.
Manfredi R, Calza L, Chiodo F.
Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Bologna, S. Orsola Hospital, Bologna, Italy.
J Cutan Pathol 2002 Mar;29(3):168-72 Abstract quote
BACKGROUND:: Cellulitis and soft tissue infection are underestimated complications of HIV disease.
PATIENTS AND METHODS: Sixty-seven bacteriologically proven consecutive episodes were identified among 2221 HIV-infected patients hospitalized in a 10-year period, and assessed according to several epidemiological, microbiological and clinical variables.
RESULTS: Staphylococcus aureus was the most frequently cultured pathogen (50% of 92 isolates), followed by Pseudomonas spp., Escherichia coli and Streptococcus pyogenes; a polymicrobial infection was present in 38.1% of episodes. Drug addiction (p < 0.003) and male gender (p < 0.04) were significantly associated with the occurrence of these complications, which were community-acquired in 83.6% of cases. While a remarkable variation in the severity of underlying immunodeficiency was shown, hematogenous dissemination occurred in 25.4% of episodes, and proved significantly related to a low CD4+ lymphocyte count, and neutropenia. A 21.7% methicillin-resistance rate was shown among S. aureus isolates. All episodes were favorably treated in 5-16 days, in over 60% of cases with associated beta-lactam-aminglycoside antibiotics; a recurrence of staphylococcal cellulitis occurred in four patients only.
CONCLUSION: Skin and soft tissue infections are continuing causes of morbidity in HIV-infected patients, even in the highly active antiretroviral therapy era.
Cardiomyopathy in AIDS: a pathophysiological perspective.
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Prog Cardiovasc Dis 2000 Sep-Oct;43(2):151-70 Abstract quote
This report addresses issues of pathogenesis, pathophysiology, and epidemiology of an increasingly prevalent cardiomyopathy in acquired immunodeficiency syndrome (AIDS). As patient survival increases with more effective antiretroviral therapy, cardiomyopathy in AIDS will become more apparent. The interactions of cellular and organism factors in AIDS and their relationships to the development of cardiomyopathy are reviewed herein.
Amongst the factors addressed in this review are: (1) comorbid conditions found with AIDS, (2) the role of inflammatory heart disease and cytokines in the development of AIDS cardiomyopathy, (3) the pathogenetic role of vascular cells and myocardial cells in the development of cardiomyopathy, (4) the role of myocardial retroviral infection in AIDS, and (5) the impact of toxicity from antiretroviral therapy on the development of cardiomyopathy. Because it is possible that more than 1 of these factors is present in a given patient inflicted with AIDS, a multifactorial pathogenesis in AIDS cardiomyopathy must be considered.
Lymphadenopathy May be early sign of AIDS Hematological abnormalities Pancytopenia common Pulmonary Unspecified pneunomia most common cause of death replacing pneumocystic carinii pneumonia GI Chronic constant diarrhea SKIN Kaposi's sarcoma
Herpes simplex and zoster
J Am Acad Dermatol. 2006 Apr;54(4):581-8. Epub 2006 Feb 23. Abstract quote
BACKGROUND: Widespread introduction of highly active antiretroviral therapy (HAART) in the mid 1990s has altered the presentation of the cutaneous manifestations associated with HIV infection.
OBJECTIVE: Our purpose was to evaluate the use of HAART on the prevalence and spectrum of cutaneous manifestations in HIV-infected patients.
METHODS: A study of the initial visits of 897 HIV-infected patients at an urban dermatology clinic between 1996 and 2002 was performed.
RESULTS: Folliculitis was the most common cutaneous disorder identified. Patients with CD4-positive cell counts less than 200 cells/mm3 had an increased prevalence of folliculitis and prurigo nodularis, whereas those with HIV viral loads higher than 55,000 copies/mL had a higher prevalence of idiopathic pruritus and candidiasis. Patients not receiving HAART had increased rates of folliculitis and prurigo nodularis. Patients receiving HAART had increased rates of photosensitivity and molluscum contagiosum.
LIMITATIONS: This was a cross-sectional study in which temporality was unable to be determined.
CONCLUSION: With ongoing therapeutic advancements, the cutaneous manifestations associated with HIV infection will continue to evolve.
Retinitis CMV Pediatric Acute and persistent bouts of diarrhea associated with rapid disease progression
Lymphoid interstitial pneumonitis, usually not found in adults
Wasting syndrome Involuntary loss of >10% of baseline body weight
Associated with disease progression and associated with poor prognosis
CHARACTERIZATION General VARIANTS BONE MARROW Changing Pattern of AIDS A Bone Marrow Study
Xiaohui Zhao, MD, PhD, Nora C.J. Sun, MD, Mallory D. Witt, MD, Margaret Keller, MD, and Yutaka Niihara, MD
Am J Clin Pathol 2004;121:393-401 Abstract quote
We compared bone marrow findings in 2 groups of patients with AIDS during 2 different periods: group 1, n = 20; male/female ratio, 19/1; and group 2, n = 120; male/female ratio, 6/1. Bone marrow iron stores were decreased significantly in group 2 ( P < .01), and the incidence of AIDS-related lymphomas was higher, with frequent bone marrow involvement.
Two group 1 patients had Kaposi sarcoma, and a 21-month-old girl with transfusion-transmitted AIDS had Burkitt-like lymphoma. In group 2, 44 patients had a history of malignant neoplasms, including Kaposi sarcoma (10 cases), hematologic neoplasms (33 cases), and metastatic leiomyosarcoma (1 case). Of the 120 patients, 15 (12.5%) had bone marrow involvement by malignant neoplasms.
The majority of the non-Hodgkin lymphomas were high-grade lymphomas. Patients with AIDS-related malignant neoplasms had higher CD4+ cell counts and viral loads than patients without malignant neoplasms ( P < .01, P < .05, respectively). The finding of decreased iron stores in patients with AIDS might aid clinical management of their anemia.
The increased incidence of malignant neoplasms, especially lymphomas, in recent years might be related to prolonged survival but with incomplete reconstitution of immune function after antiretroviral therapy.
The Histopathology of 103 Consecutive Colonoscopy Biopsies From 82 Symptomatic Patients With Acquired Immunodeficiency Syndrome Original and Look-Back Diagnoses
Jan Marc Orenstein, MD, PhD and Douglas T. Dieterich, MD
From the Department of Pathology, George Washington University Medical Center, Washington, DC (Dr Orenstein); and the Department of Medicine, Division of Gastroenterology, New York University School of Medicine, New York, NY (Dr Dieterich)
Arch Pathol Lab Med 2001;125:1042–1046. Abstract quote
Objective. —To compare the primary diagnoses assigned by general surgical pathologists on a series of 103 consecutive colon biopsies from individuals infected with human immunodeficiency virus (HIV) with diagnoses rendered by a pathologist with extensive experience in gastrointestinal pathology in HIV/acquired immunodeficiency syndrome.
Design. —New sections were cut from paraffin blocks of 103 consecutive colon biopsies taken during colonoscopies of 82 different HIV-infected patients; all new sections were stained with hematoxylin-eosin. These individuals either had negative stool studies or had failed to respond to therapy and had chronic large bowel symptoms, such as frequent small volume–type diarrhea, tenesmus, and/or bright red blood per rectum. Immunohistochemistry for cytomegalovirus (CMV) was performed on 18 of 22 specimens originally diagnosed with CMV colitis.
Results.—The initial study yielded 70 (68%) negative or nonspecific diagnoses, 22 (21%) cases of CMV colitis, 5 (5%) Cryptosporidium diagnoses, 2 cases each of adenomatous polyps and Kaposi sarcoma, and 1 case each of spirochetosis and squamous cell carcinoma of the anorectum. Review of the recuts yielded 64 (62%) negative or nonspecific diagnoses, 12 (12%) new adenovirus infections (3 combined with CMV), and 11 (11%) lone CMV infections. Three attaching and effacing bacterial infections were diagnosed, 1 with adenovirus coinfection. A total of 4 spirochetosis cases were found on review. Seven (7%) of the biopsies showed at least 1 coinfection. Nine biopsies had features suggestive of inflammatory bowel disease.
Conclusions. —Colonoscopy with biopsy after negative stool studies or failure to respond to therapy yielded a high proportion of negative or nonspecific diagnoses. Adenovirus and enteropathogenic bacterial infections had been totally overlooked on initial examination. It takes particular experience to evaluate gastrointestinal biopsies from HIV-infected patients.
Human Immunodeficiency Virus (HIV)-Associated Polymorphic Lymphoproliferative Disorders.
Nador RG, Chadburn A, Gundappa G, Cesarman E, Said JW, Knowles DM.
Am J Surg Pathol 2003 Mar;27(3):293-302 Abstract quote
The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic lymphomas. In contrast, the lymphoid proliferations arising in solid organ transplant recipients, collectively referred to as posttransplantation lymphoproliferative disorders (PT-LPDs), represent a clinically and histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell proliferations of variable clonal composition.
During a retrospective histopathologic review of lymphoid proliferations associated with human immunodeficiency virus (HIV) infection we identified 10 cases that morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes (five), lungs (two), and the parotid gland, perineum, and skin (one each). They exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell population exhibiting a variable degree of plasmacytic differentiation, cytologic atypia, and numbers of atypical immunoblasts. A clonal B-cell population was detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The nongermline hybridizing bands were usually faint, however, suggesting that the clonal B-cell population represented only a subpopulation within the polymorphic lesion. Strong clonal rearrangement bands were present in one case in which there was clear morphologic evidence of transformation to diffuse large cell lymphoma. This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6, RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10 (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma-associated herpesvirus was detectable in two cases by polymerase chain reaction analysis, but not by Southern blotting. In situ hybridization demonstrated Kaposi's sarcoma-associated herpesvirus in some of the cytologically malignant-appearing cells.
In conclusion, polymorphic B-cell lymphoproliferative disorders comparable morphologically and molecularly to those arising after solid organ transplantation also occur in association with HIV infection. As in the case of their polymorphic PT-LPD counterparts, their malignant status, biologic significance, and relationship to monomorphic B-cell lymphomas remain to be elucidated.
J Am Acad Dermatol. 2006 Feb;54(2):189-206; quiz 207-10. Abstract quote
Certain skin cancers occur with increased frequency or altered course in patients infected with HIV. Malignant melanoma and squamous cell carcinoma are examples of cutaneous malignancies that have a more aggressive course in patients with HIV. Others, such as basal cell carcinoma, appear more frequently in this population but do not appear to be more aggressive. The incidence of HIV-associated Kapsosi's sarcoma has markedly decreased since the advent of HIV antiretroviral therapy.
Our understanding of the pathogenesis of this malignancy and its unique management issues are fully reviewed. Cutaneous T-cell lymphoma (CTCL) is rare in this population. Other types of cutaneous lymphoma and HIV-associated pseudo-CTCL are discussed. This article addresses prevention, treatment, and follow-up strategies for this at-risk population.
LEARNING OBJECTIVE: At the completion of this learning activity, participants should be familiar with the unique epidemiology, clinical course, and management of cutaneous malignancy in patients infected with HIV.
The histopathology of folliculitis in HIV-infected patients
Rona Beth Holmes1, Ciro Martins2 and Thomas Horn1
J Cutan Pathol 2002;29:93-95 Abstract quote
Background:Cutaneous disease referable to human immunodeficiency virus (HIV) infection has become less common with the advent of widespread administration of antiretroviral medications, particularly the protease inhibitors. Pruritic eruptions that fall into the general categorization of folliculitis continue to be problematic.
Methods:In this report, we describe 33 skin biopsy samples prospectively obtained of follicular papules and pustules from 33 HIV-infected individuals with the clinical diagnosis of HIV-related folliculitis.
Results:The histopathologic findings were stratified as follows: (i) acute folliculitis with bacteria and/or yeast (n=9); (ii) lymphocytic perifolliculitis (n=7); (iii) eosinophilic folliculitis (n=5); (iv) perifolliculitis with mixed inflammation (n=11); (v) follicular rupture with predominant granulomatous inflammation (n=1). Demodex organisms were found in 10 specimens scattered among these categories.
Conclusions:The histopathology of folliculitis in HIV-infected patients is protean. No single factor could be identified as the cause, making targeted antibacterial or antifungal therapy unlikely to be successful across a wide range of patients.
The AIDS autopsy spleen: a comparison of the pre-anti-retroviral and highly active anti-retroviral therapy eras.
Diaz LK, Murphy RL, Phair JP, Variakojis D.
Department of Pathology, Northwestern University Medical School and Northwestern Memorial Hospital, Chicago, Illinois 60611, USA.
Mod Pathol 2002 Apr;15(4):406-12 Abstract quote
Pathologic findings attributed to human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) are described in the spleen in studies that encompassed the years preceding highly active anti-retroviral therapy (HAART).
Major findings included white-pulp depletion, hemosiderin deposition, spindle cell proliferations, and perivascular hyalinization. Infectious and malignant infiltrates were commonly noted and characterized. The histopathology of AIDS autopsy spleens since the introduction of protease inhibitors has not been studied. Histologic sections from 168 cases of AIDS spleens examined at autopsy over a 19-year period (1982-2000) were evaluated for significant pathologic findings. Multiple morphologic parameters were recorded, including a graded estimation of white-pulp depletion. Significantly less white-pulp depletion was observed in the 39 HAART-era spleens (1995-2000) compared with the 129 spleens from the 1982-1994 patient group (P =.001).
The rates of splenic involvement by atypical mycobacteria and cytomegalovirus were similar to those in the past, although the overall clinical rates of these opportunistic infections were found to be decreased. The annual numbers of AIDS autopsies have decreased, reflecting a nationwide trend of lower autopsy rates. Increased survival with HIV infection and AIDS is now apparent. Protease inhibitors, in conjunction with other contemporary therapies, may have contributed to the preservation of white pulp observed in the HAART patient group.
Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas.
Carbone A, Gloghini A, Larocca LM, Capello D, Pierconti F, Canzonieri V, Tirelli U, Dalla-Favera R, Gaidano G.
Divisions of Pathology and Medical Oncology A, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, Italy.
Blood 2001 Feb 1;97(3):744-51 Abstract quote
This study was aimed at defining the histogenesis of the pathologic spectrum of lymphoma arising in the context of human immunodeficiency virus (HIV) infection.
Toward this aim, 87 AIDS-related non-Hodgkin lymphomas (AIDS-NHL) and 16 Hodgkin lymphomas arising in HIV+ patients (HIV-HL) were comparatively analyzed for the expression pattern of several B-cell histogenetic markers, including BCL-6 (expressed by centroblasts and centrocytes),
MUM1/IRF4 (expressed by late centrocytes and post-germinal center [GC] B cells), and CD138/syn-1 (expressed by post-GC B cells). Expression of MUM1, BCL-6, and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and HIV-HL: (1) the BCL-6+/MUM1-/syn-1- pattern, selectively clustering with a large fraction of AIDS-Burkitt lymphoma (17 of 19) and of systemic AIDS-diffuse large cell lymphoma (12 of 16); (2) the BCL-6-/MUM1+/syn-1- pattern, associated with a fraction of AIDS-immunoblastic lymphoma (8 of 24); and (3) the BCL-6-/MUM1+/syn-1+ pattern, associated with systemic and primary central nervous system immunoblastic lymphoma (14 of 24) and with primary effusion lymphoma (10 of 10), plasmablastic lymphoma of the oral cavity (7 of 7), and HIV-HL (15 of 16).
Analysis of nonneoplastic lymph nodes showed that the 3 phenotypic patterns detected in AIDS-NHL and HIV-HL correspond to distinct stages of physiologic B-cell development-centroblasts (BCL-6+/MUM1-/syn-1-), late GC/early post-GC B cells (BCL-6-/MUM1+/syn-1-), and post-GC B cells (BCL-6-/MUM1+/syn-1+). Expression of the Epstein-Barr virus-encoded latent membrane protein-1 clustered with the BCL-6-/MUM1+/syn-1+ profile throughout the clinicopathologic spectrum of AIDS-NHL and HIV-HL.
Overall, these results define novel histogenetic subsets of AIDS-NHL and HIV-HL and may provide novel tools for refining the diagnosis of these disorders.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS GENERAL
Autopsy Findings in a Human Immunodeficiency VirusInfected Population Over 2 Decades
Influences of Gender, Ethnicity, Risk Factors, and Time
Susan Morgello, MD, Rashid Mahboob, MD, Tatiana Yakoushina, MD, Shafat Khan, MD, and Karin Hague, MD
From the Manhattan HIV Brain Bank, Department of Pathology, Division of Neuropathology, the Mount Sinai Medical Center, New York, NY
Arch Pathol Lab Med 2002;Vol. 126, No. 2, pp. 182190. Abstract quote
Objectives.To examine autopsy pathology in an urban population infected with the human immunodeficiency virus (HIV) and to determine if age at death and disease frequencies are associated with gender, HIV risk factors, ethnicity, and therapeutic era.
Design and Methods.Retrospective analysis of autopsy data from 394 HIV-infected adults. The population was divided into 3 therapeutic eras for analysis: group A, 19791986; group B, 19871995; and group C, 19962000.
Results.Women died at significantly younger ages than men (mean ± SEM age, 38.9 ± 1.0 years vs 42.5 ± 0.64 years), even after adjustment for risk factors, ethnicity, and therapeutic era. This age discrepancy occurred despite a lower prevalence of arteriosclerosis, cachexia, and hepatitis B in women and no significant differences in the frequencies of other infectious diseases. Whites had a longer survival than patients of other ethnicities (mean age at death, 44.7 ± 1.2 years for whites, 39.9 ± 0.80 years for blacks, and 41.3 ± 0.87 years for Hispanic individuals). Renal, cardiac, and splenic pathologies, Mycobacterium avium-intracellulare (MAI) infection, and cachexia were more common in blacks than in whites and/or Hispanic individuals, and cytomegalovirus and systemic lymphoma were more common in whites and Hispanic individuals than in blacks. Diseases associated with intravenous drug use were hepatitis C, cirrhosis, and tuberculosis; those with all sexual risk factors, cytomegalovirus infection, herpes simplex virus infection, and Pneumocystis carinii pneumonia; and those with homosexual risk, Kaposi sarcoma and MAI infection. The prevalence of many disease entities changed over time: compared with the other groups, group C had lower prevalences of many viral and fungal illnesses, MAI infection, systemic lymphoma, cachexia, and Kaposi sarcoma and higher prevalences of hepatitis, cirrhosis, arteriosclerosis, staphylococcal and streptococcal infections, and traumatic lesions. When the data were adjusted for changing demographic and risk composition, the only significant changes in disease frequency for period C were decreased prevalences of PCP and Kaposi sarcoma and increased prevalences of cirrhosis and arteriosclerosis.
Conclusions.Significant gender- and ethnicity-related differences in age of death occurred in this HIV-infected population, and these differences were not explained by the frequencies of diseases. The lower prevalences of PCP and Kaposi sarcoma in group C are likely a reflection of the impact of potent therapies on causes of mortality. The higher prevalences of cirrhosis and arteriosclerosis suggest that entities not targeted by antiretroviral reconstitution of immunity will play an increasingly important role in HIV-related mortality in the future.
Risk factors for pediatric human immunodeficiency virus-related malignancy.
Pollock BH, Jenson HB, Leach CT, McClain KL, Hutchison RE, Garzarella L, Joshi VV, Parmley RT, Murphy SB.
Children's Cancer Research Institute.
JAMA 2003 May 14;289(18):2393-9 Abstract quote
CONTEXT: Although cancers occur with increased frequency in children with human immunodeficiency virus (HIV) infection, the specific clinical, immunological, and viral risk factors for malignancy have not been identified.
OBJECTIVE: To identify risk factors for malignancy among HIV-infected children.Design, Setting, and
PATIENTS: A multicenter case-control study of children with HIV at 26 institutions participating in the Pediatric Oncology Group. Forty-three case patients with a new malignancy and 74 control patients without a malignancy were matched based on the duration of their infection. Patients were enrolled between January 1992 and July 1998.
MAIN OUTCOME MEASURES: Clinical and laboratory factors assessed as putative risk factors included demographic characteristics, HIV characteristics, prior antiretroviral treatment, and CD4 cell count. Coviral infections with Epstein-Barr virus (EBV), cytomegalovirus, and human herpesvirus 6 were assessed by semiquantitative polymerase chain reaction assays and serological testing.
RESULTS: Case malignancy diagnoses included 28 non-Hodgkin lymphoma, 4 B-cell acute lymphoblastic leukemia, 1 Hodgkin disease, 8 leiomyosarcoma, 1 hepatoblastoma, and 1 schwannoma. Epstein-Barr virus viral load of more than 50 viral genome copies per 105 peripheral blood mononuclear cells was strongly associated with cancer risk but only for children with CD4 cell counts of at least 200/ micro L (odds ratio [OR], 11.33; 95% confidence interval [CI], 2.09-65.66, P<.001). High EBV viral load was not associated with cancer for children with CD4 cell counts of less than 200/ micro L (OR, 1.12; 95% CI, 0.13-9.62; P =.99). Zidovudine antiretroviral therapy did not confer a significant protective effect for either the high (OR, 0.81; 95% CI, 0.22-3.09; P =.77) or the low CD4 cell count groups (OR, 0.27; 95% CI, 0.04-1.46; P =.16). The route of HIV infection was not associated with increased cancer risk.
CONCLUSIONS: Route of infection, demographic characteristics, and zidovudine use were not associated with the development of malignancy in HIV-infected children. High viral burden with EBV was associated with the development of malignancy in HIV-infected children although the effect was modified by CD4 cell count. The pathogenesis of HIV-related pediatric malignancies remains unclear and other contributing risk factors can be elucidated only through further study.
PLASMA HIV-1 RNA
Initial Plasma HIV-1 RNA Levels and Progression to AIDS in Women and Men
Timothy R. Sterling, M.D., David Vlahov, Ph.D., Jacquie Astemborski, M.H.S., Donald R. Hoover, Ph.D., M.P.H., Joseph B. Margolick, M.D., Ph.D., and Thomas C. Quinn, M.Dng
N Engl J Med 2001;344:720-725 Abstract quote
It is unclear whether there are differences between men and women with human immunodeficiency virus type 1 (HIV-1) infection in the plasma level of viral RNA (the viral load). In men, the initial viral load after seroconversion predicts the likelihood of progression to the acquired immunodeficiency syndrome (AIDS), but the relation between the two has not been assessed in women. Currently, the guidelines for initiating antiretroviral therapy are applied uniformly to women and men.
From 1988 through 1998, the viral load and the CD4+ lymphocyte count were measured approximately every six months in 156 male and 46 female injection-drug users who were followed prospectively after HIV-1 seroconversion.
The median initial viral load was 50,766 copies of HIV-1 RNA per milliliter in the men but only 15,103 copies per milliliter in the women (P<0.001). The median initial CD4+ count did not differ significantly according to sex (659 and 672 cells per cubic millimeter, respectively). HIV-1 infection progressed to AIDS in 29 men and 15 women, and the risk of progression did not differ significantly according to sex. For each increase of 1 log in the viral load (on a base 10 scale), the hazard ratio for progression to AIDS was 1.55 (95 percent confidence interval, 0.97 to 2.47) among the men and 1.43 (95 percent confidence interval, 0.76 to 2.69) among the women. The median initial viral load was 77,822 HIV-1 RNA copies per milliliter in the men in whom AIDS developed and 40,634 copies per milliliter in the men in whom it did not; the corresponding values in the women were 17,149 and 12,043 copies per milliliter. Given the recommendation that treatment should be initiated when the viral load reaches 20,000 copies per milliliter, 74 percent of the men but only 37 percent of the women in our study would have been eligible for therapy at the first visit after seroconversion (P<0.001).
Although the initial level of HIV-1 RNA was lower in women than in men, the rates of progression to AIDS were similar. Treatment guidelines that are based on the viral load, rather than the CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex.
Interventions to prevent HIV risk behaviors.
National Institutes of Health Consensus Development Conference Statement February 11-13, 1997.
AIDS 2000 Sep;14 Suppl 2:S85-96 Abstract quote
OBJECTIVE: To provide health care providers, patients, and the general public with a responsible assessment of behavioral intervention methods that may reduce the risk of HIV infection.
PARTICIPANTS: A non-Federal, nonadvocate, 12-member panel representing the fields of psychiatry, psychology, behavioral and social science, social work, and epidemiology. In addition, 15 experts in psychiatry, psychology, behavioral and social science, social work, and epidemiology presented data to the panel and a conference audience of 1000.
EVIDENCE: The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience.
CONSENSUS PROCESS: The panel, answering predefined questions, developed its conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference.
CONCLUSIONS: Behavioral interventions to reduce risk for HIV/AIDS are effective and should be disseminated widely. Legislative restriction on needle exchange programs must be lifted because such legislation constitutes a major barrier to realizing the potential of a powerful approach and exposes millions of people to unnecessary risk. Legislative barriers that discourage effective programs aimed at youth must be eliminated. Although sexual abstinence is a desirable objective, programs must include instruction on safer sex behaviors. The erosion of funding for drug abuse treatment programs must be halted because research data clearly show that such programs reduce risky drug abuse behavior and often eliminate drug abuse itself. Finally, new research must focus on emerging risk groups such as young people, particularly those who are gay and who are members of ethnic minority groups, and women, in whom transmission of HIV virus to their children remains a major public health problem.
Randomized, controlled phase II trial of subcutaneous interleukin-2 in combination with highly active antiretroviral therapy (HAART) in HIV patients.
Hengge UR, Goos M, Esser S, Exner V, Dotterer H, Wiehler H, Borchard C, Muller K, Beckmann A, Eppner MT, Berger A, Fiedler M.
Department of Dermatology and Venerology, University of Essen, Germany.
AIDS 1998 Dec 3;12(17):F225-34 Abstract quote
OBJECTIVE: To determine the immunological, virological and clinical effects of subcutaneous IL-2 in 44 HIV-patients in conjunction with pre-existing tri-therapy (zidovudine, 3TC, saquinavir). DESIGN: Partially randomized, controlled, prospective trial.
SETTING: Single center study at tertiary care center.
PATIENTS: Sixty four patients (CD4 count 200-500 x 10(6)/l).
INTERVENTION: Fourty four patients were randomized to receive 5-day cycles of IL-2 (9 Mio IU/d) every 6 weeks (Group A) or whenever the CD4 cell count dropped below the 1.25-fold of baseline (Group B), whereas 20 control patients received the same HAART without IL-2. Outcome measures: The optimal individual treatment interval and the immunological and virological effects of subcutaneously administered IL-2 were analysed. Importantly, the level of cellular in vivo immunity and the frequency of dermatological marker diseases and infectious complications were assessed.
RESULTS: IL-2 was well tolerated although fever, influenza-like symptoms and indurated injection sites were commonly encountered. After 1 year of IL-2, there was a median increase of more than 100 x 10(6)/l CD4 cells in both IL-2 groups in contrast to the controls (P < 0.01, 0.01 and not significant). The median HIV load did not increase either in plasma or in lymph nodes. Lymphocyte activation decreased as assessed by MHC class II (P < 0.001), CD25 (P < 0.001) and CD38 expression (P ¥ 0.005). Although delayed type hypersensitivity against common recall antigens increased in both IL-2 groups, it did not reach statistical significance. However, it is of note, that in 7 of 11 (63.6%) patients delayed type hypersensitivity against recombinant HIV antigens improved significantly. Whereas there was no opportunistic infection in either IL-2 group, three cases of Kaposi's sarcoma occurred in the controls. Dermatological indicator diseases (thrush, condyloma, herpes simplex) were found to occur more frequently in the control group.
CONCLUSIONS: Subcutaneous IL-2 in addition to HAART was safe and led to sustained qualitative and quantitative immunological improvements in the majority of patients. Individualisation of therapy intervals further improved the efficacy and tolerance of IL-2.
High dose therapy and autologous stem cell transplantation for human immunodeficiency virus-associated non-Hodgkin lymphoma in the era of highly active antiretroviral therapy.
Molina A, Krishnan AY, Nademanee A, Zabner R, Sniecinski I, Zaia J, Forman SJ.
Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, California 91010, USA.
Cancer 2000 Aug 1;89(3):680-9 Abstract quote
BACKGROUND: The advent of highly active antiretroviral therapy (HAART) has allowed the exploration of more dose-intensive therapy such as autologous stem cell transplantation (ASCT) in selected patients with human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL).
METHODS: The authors report on the use of myeloablative chemotherapy with ASCT in two HIV positive patients with NHL. The first patient underwent ASCT at the time of first disease remission for poor risk, diffuse, large cell NHL and the second patient had multiply recurrent, chemosensitive Burkitt lymphoma. ASCT was performed in both patients using a transplant conditioning regimen of high dose cyclophosphamide, carmustine, and etoposide (CBV).
RESULTS: The target dose of >/= 5 x 10(6)/kg CD34 positive peripheral blood stem cells (PBSC) utilized for ASCT was collected using granulocyte-colony stimulating factor (G-CSF) after chemotherapy for mobilization while both patients were receiving concomitant HAART for HIV infection. HAART was continued during CBV conditioning. Prompt hematopoietic recovery was observed after ASCT. Both patients remained in clinical disease remission from their lymphoma at 28 months and 20 months after transplant, respectively.
CONCLUSIONS: ASCT is feasible in patients with HIV-associated NHL. Adequate numbers of CD34 positive PBSC can be procured from patients receiving HAART and chemotherapy for NHL. Selected patients with HIV-related lymphoma can tolerate the high dose CBV myeloablative chemotherapy regimen without increased acute regimen-related toxicity. Reinfusion of G-CSF-mobilized PBSC can lead to rapid recovery of hematologic function and sustained engraftment after ASCT. Given the poor prognosis of patients with HIV-associated NHL treated with conventional chemotherapy, further investigation of this approach should be considered.
Prospective randomized two-Arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy.
Tuldra A, Fumaz CR, Ferrer MJ, Bayes R, Arno A, Balague M, Bonjoch A, Jou A, Negredo E, Paredes R, Ruiz L, Romeu J, Sirera G, Tural C, Burger D, Clotet B.
HIV Unit, "Fundacio Lluita SIDA" and "IrsiCaixa" Retrovirology Laboratory, "Germans Trias i Pujol" University Hospital, Badalona, Spain.
J Acquir Immune Defic Syndr 2000 Nov 1;25(3):221-8 Abstract quote
BACKGROUND: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long-term period of therapy are necessary.
METHODS: This is a prospective, randomized, two-arm controlled study including patients starting their first-or second-line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow-up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long-term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long-term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self-reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of >/=95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods.
RESULTS: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence >/=95% (p =.008); 89% of patients in the EG versus 66% controls had HIV-1 RNA levels <400 copies/ml (p =.026). Overall, 85% of patients with adherence >/=95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p =. 008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p =.04), poor effort to take medication (OR, 5.38; p =.03), and high self-perceived capacity to follow the regimen (OR, 13.76; p =.04). Self-reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG.
CONCLUSIONS: Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patient's compliance in the clinical setting.
Long-term impact of highly active antiretroviral therapy on HIV-related health care costs.
Keiser P, Nassar N, Kvanli MB, Turner D, Smith JW, Skiest D.
The University of Texas Southwestern Medical Center at Dallas, and Department of Veterans Affairs Medical Center, Dallas, Texas, USA.
J Acquir Immune Defic Syndr 2001 May 1;27(1):14-9 Abstract quote
CONTEXT: Highly active antiretroviral therapy (HAART) is associated with decreased opportunistic infections, hospitalization, and HIV-related health care costs over relatively short periods of time. We have previously demonstrated that decreases in total HIV cost are proportional to penetration of protease inhibitor therapy in our clinic.
OBJECTIVE: To determine the effects of HAART on HIV health care use and costs over 44 months.
SETTING: A comprehensive HIV service within a Veterans Affairs Medical Center.
DESIGN: A cost-effectiveness analysis of HAART.
MAIN OUTCOME MEASUREMENTS: The mean monthly number of hospital days, infectious diseases clinic visits, emergency room visits, non-HIV-related outpatient visits, inpatient costs, and antiretroviral treatment costs per patient were determined by dividing these during the period from January 1995 through June 1998 into four intervals. Viral load tests were available from October 1996. Cost-effectiveness of HAART was evaluated by determining the costs of achieving an undetectable viral load over time.
RESULTS: Mean monthly hospitalization and associated inpatient costs decreased and remained low 2 years after the introduction of protease inhibitors (37 hospital days per 100 patients). Total cost decreased from $1905 per patient per month during the first quarter to $1090 per patient per month in the third quarter but increased to $1391 per patient per month in the fourth quarter. Antiretroviral treatment costs increased throughout the entire observation period from $79 per patient per month to $518 per patient per month. Hospitalization costs decreased from $1275 per patient per month in the first quarter to less than $500 per patient per month in each of the third and fourth quarters. The percentage of patients with a viral load <500 copies/mL increased from 21% in October 1996 to 47% in June of 1997 (p =.014). The cost of achieving an undetectable viral load decreased from $4438 per patient per month to $2669 per patient per month, but this trend did not reach statistical significance (p =.18).
CONCLUSIONS: After an initial decrease, there was an increase in the total monthly cost of caring for HIV patients. Cost increases were primarily due to antiretroviral treatment costs, but these costs were offset by a marked decrease in inpatient-related costs. Increases in costs were not related to antiretroviral treatment failures as measured by the proportion of patients with low or undetectable viral loads. The cost of achieving an undetectable viral load remained stable despite increases in the cost of procuring antiretroviral agents.
Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.
Shiver JW, Fu TM, Chen L, Casimiro DR, Davies ME, Evans RK, Zhang ZQ, Simon AJ, Trigona WL, Dubey SA, Huang L, Harris VA, Long RS, Liang X, Handt L, Schleif WA, Zhu L, Freed DC, Persaud NV, Guan L, Punt KS, Tang A, Chen M, Wilson KA, Collins KB, Heidecker GJ, Fernandez VR, Perry HC, Joyce JG, Grimm KM, Cook JC, Keller PM, Kresock DS, Mach H, Troutman RD, Isopi LA, Williams DM, Xu Z, Bohannon KE, Volkin DB, Montefiori DC, Miura A, Krivulka GR, Lifton MA, Kuroda MJ, Schmitz JE, Letvin NL, Caulfield MJ, Bett AJ, Youil R, Kaslow DC, Emini EA.
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Nature 2002 Jan 17;415(6869):331-5 Abstract quote
Recent studies of human immunodeficiency virus type 1 (HIV-1) infection in humans and of simian immunodeficiency virus (SIV) in rhesus monkeys have shown that resolution of the acute viral infection and control of the subsequent persistent infection are mediated by the antiviral cellular immune response.
We comparatively assessed several vaccine vector delivery systems-three formulations of a plasmid DNA vector, the modified vaccinia Ankara (MVA) virus, and a replication incompetent adenovirus type 5 (Ad5) vector-expressing the SIV gag protein for their ability to elicit such immune responses in monkeys. The vaccines were tested either as a single modality or in combined modality regimens.
Here we show that the most effective responses were elicited by a replication-incompetent Ad5 vector, used either alone or as a booster inoculation after priming with a DNA vector. After challenge with a pathogenic HIV-SIV hybrid virus (SHIV), the animals immunized with Ad5 vector exhibited the most pronounced attenuation of the virus infection.
The replication-defective adenovirus is a promising vaccine vector for development of an HIV-1 vaccine.
Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes.
Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl FW, Krivulka GR, Beaudry K, Lifton MA, Gorgone DA, Montefiori DC, Lewis MG, Wolinsky SM, Letvin NL.
Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Research East Room 113, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Nature 2002 Jan 17;415(6869):335-9 Abstract quote
Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited by candidate AIDS vaccines have recently been shown to control viral replication and prevent clinical disease progression after pathogenic viral challenges in rhesus monkeys.
Here we show that viral escape from CTL recognition can result in the eventual failure of this partial immune protection. Viral mutations that escape from CTL recognition have been previously described in humans infected with human immunodeficiency virus (HIV) and monkeys infected with simian immunodeficiency virus (SIV). In a cohort of rhesus monkeys that were vaccinated and subsequently infected with a pathogenic hybrid simian-human immunodeficiency virus (SHIV), the frequency of viral sequence mutations within CTL epitopes correlated with the level of viral replication. A single nucleotide mutation within an immunodominant Gag CTL epitope in an animal with undetectable plasma viral RNA resulted in viral escape from CTLs, a burst of viral replication, clinical disease progression, and death from AIDS-related complications.
These data indicate that viral escape from CTL recognition may be a major limitation of the CTL-based AIDS vaccines that are likely to be administered to large human populations over the next several years.
Norvartis Research Institute, PO Box 80, Brunner Strasse 59, 1235 Vienna, Austria.
Curr Opin Investig Drugs 2001 Sep;2(9):1203-8 Abstract quote
AIDSVAX, a bivalent vaccine consisting of a preparation of recombinant gp120 from two types of HIV, is being developed by VaxGen for the potential prevention of HIV infection . Two versions of the vaccine are in phase III trials: AIDSVAX B/E, in phase III trials in Thailand, stimulates production of antibodies to HIV subtypes common to South and Southeast Asia, and countries of the Pacific Rim; and AIDSVAX B/B, in phase III trials in the US and Europe, stimulates production of antibodies to HIV subtypes that are found in the Americas, Europe, the Caribbean and Australia , . The bivalent vaccine is based on an earlier monovalent vaccine, MNrgp120 (Genetech Inc/VaxGen Inc) , .
In April 2001, the independent data and safety monitoring board (DSMB) reviewed data from the trials and indicated that the vaccine appeared safe and that the trials were being conducted appropriately. VaxGen has disclosed that an average of 95% of volunteers continue to participate in the phase III trials. The DSMB was scheduled to conduct its review in November 2001, to examine the efficacy of AIDSVAX in the prevention of HIV infection. VaxGen would halt the trial early if the interim analysis shows the vaccine to be effective. The company would then begin the process of applying for regulatory approval.
If the interim analysis proves inconclusive, the trial would proceed to its scheduled conclusion in the fourth quarter of 2002 , . In August 1998, a collaborative research agreement was signed with the National Institute of Allergy and Infectious Diseases (NIAID). This includes research on combinations of AIDSVAX and other NIAID vaccines and research for new formulations suitable for developing nations .
Advancing AIDSVAX to phase 3. Safety, immunogenicity, and plans for phase 3.
Francis DP, Gregory T, McElrath MJ, Belshe RB, Gorse GJ, Migasena S, Kitayaporn D, Pitisuttitham P, Matthews T, Schwartz DH, Berman PW.
VaxGen, Inc., South San Francisco, California 94080, USA
AIDS Res Hum Retroviruses 1998 Oct;14 Suppl 3:S325-31 Abstract quote
AIDSVAX (VaxGen, Inc., South San Francisco, CA), a possible vaccine to protect against human immunodeficiency virus type 1 (HIV-1) infection, is being tested for efficacy in phase 3 studies. It has been tested for potential efficacy in chimpanzees, and tested for safety and immunogenicity in human clinical studies. Four candidate vaccines, each with a different envelope protein antigen or combination of antigens, have been produced in alum formulations. In both design and clinical testing, AIDSVAX has an excellent safety profile. Because these highly purified proteins were prepared using recombinant DNA technology, there is no possibility of these vaccines causing HIV infection.
Having been administered to over 1200 people, the only side effects attributable to AIDSVAX have been local pain and inflammation at the injection site. After immunization, essentially all recipients developed a robust antibody response, including binding and neutralizing antibodies. The neutralizing antibodies peaked after a 12-month boost. Excellent memory is induced.
Two phase 3 trials of two bivalent formulations will evaluate their efficacy. One trial will use a bivalent subtype B formulation. This trial in North America will involve 5000 men who have sex with men and heterosexual women at high risk. The other study will use a bivalent subtype B/subtype E formulation. This trial in Thailand and will involve 2500 intravenous drug users. Both studies will be randomized, double-blinded and placebo controlled. The volunteers will be followed for 3 years.
The end points of the studies are infection, as defined by seroconversion to standard diagnostic tests, and viral load, as defined by commercial polymerase chain reaction (PCR) tests.
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EIA-Enzyme Immunoassay. This is the initial screening test for the HIV-1. Antibodies directed against the HIV-1 antibody are tagged with a marker. If the serum contains the HIV-1 antibody, it will react.
Retrovirus-This is the class of virus that encompasses HIV-1. These viruses are distinguished by a reverse transcriptase enzyme that allows the virus to utilize the infected cell's own genetic machinery to replicate itself.
Western Blot-This is the confirmatory test which is run if the initial screening EIA test for HIV-1 is positive. The patient's serum is run on an electrophoresis gel and reacted with probed directed against the antibody.
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