Abstract Book Vol. 2 [International Conference on AIDS (14th: 2002: Barcelona, Spain)]

XIV International AIDS Conference

Abstracts WePeA5767-WePeA5770 19

WePeA5767 HIV-1-specific CD8+ T cell responses contribute to
the differential HIV disease progression in
HIV-1 -infected individuals with variable HLA-B35
genotype
X. Jin', X.J. Gao2, M. Ramanathan3, G.R. Deschenes3, G. Nelson2,
S.J. O'Brien4, D.D. Ho3, T.R. O'Brien5, M. Carrington2. IUniv of Rochester, 601
Elmwood Avenue, Room, 35103, Box 689, Rochester, NY 14642, United States;
2SAIC, Frederick, United States; 3Aaron Diamond AIDS Res. Ctr., New York,
United States; 4Lab. of Genomic Diversity NCI, Frederick, United States; 5 Viral
Epidemiology Br, NCI, Frederick, United States
Background: Our previous data indicate that HIV-1 -infected individuals with certain HLA-B*35 allelic variants (B*3502/3503/3504/5301) (B*35-Px) have more
rapid disease progression than those with the B*3501/3508 (B*35-PY). The
mechanisms responsible for this phenomenon are not clear.
Methods: To examine whether cellular immune responses may different according to the HLA-B*35 genotype, we quantified HIV-1 -specific CD8+ T cell (CTL)
responses using an intracellular cytokine-staining assay in the 32 HIV-1 positive
individuals who have the B*35 alleles.
Results: In the subjects we studied, 75% had CTL responses to Pol, 69% to
Gag, 50% to Nef and 41% to Env. Although the magnitude of CTL responses did
not differ between patients bearing the B*35-PY genotype and those bearing the
B*35-Px genotypes, there was a highly significant inverse correlation (p=0.009)
between plasma HIV-1 RNA levels and the Gag-specific CTL numbers in individuals with B*35-PY, but not with B*35-Px. Furthermore, a negative correlation between CTL activity for each of the four HIV antigens and viral load was observed
among individuals with B*35-PY, whereas the relationship was always positive for
the B*35-Px group. While these correlations were not significant in most cases, a
significant difference between the B*35-PY and B*35-Px groups in their correlation values for total CTL activity and viral load was observed (p<0.05).
Conclusions: Our results suggest that the viral-specific CTL may be protective
against HIV disease progression in infected-individuals with the B*35-PY, but not
the B*35-Px genotype.
Presenting author: Xia Jin, 601 Elmwood Avenue, Room, 35103, Box 689,
Rochester, NY 14642, United States, Tel.: [phone], Fax: [phone], E-mail: XiaJin @ URMC.Rochester.edu
WePeA5768 Association of the NRAMP1 gene with modified
risk to human immunodeficiency virus
susceptibility in South Africa
D. Pretorius', M. Zeier', E. Vorster2, A. Kruger2, C. Venter2, M.J. Kotze3.
'Human Genetics, Faculty of Health Sciences, University of Stellenbosch,
Tygerberg, Cape Town, South Africa; 2University of Potchefstroom,
Potchefstroom, South Africa; 3University of Stellenbosch, Stellenbosch, South
Africa
Background: The complexity of interaction between infectious agents and host
cells raises the possibility that genetic variants of any of the host molecules
involved in host response to infection might affect clinical outcome in HIV
seropositive subjects. The natural resistance-associated macrophage protein-1
(NRAMP1) gene analysed in this study has been implicated in iron transport and
is associated with both infectious and autoimmune disease susceptibility.
Methods: DNA samples of 314 HIV-positive subjects and 336 healthy population
matched controls were subjected to screening of two apparently functional polymorphisms in the NRAMP1 gene using polymerase chain reaction (PCR)-based
methods.
Results: The allele frequency and genotype distribution of the 5'-GT repeat in
the promoter region of the NRAMP1 gene differed significantly between HIVseropositive patients attending an infectious diseases clinic in Cape Town, South
Africa, and population-matched controls (P<0.05) while no differences were detected between asymptomatic HIV-infected subjects and controls. Further, analysis of the 9-bp deletion in exon 2 of the NRAMP1 gene, previously shown to be
associated with susceptibility to HIV-1 infection in sub-Saharan Africans, indicated
no association with modified risk to HIV infection in our study population.
Conclusions: Failure to demonstrate association of the 5'-GT repeat polymorphism with risk of HIV infection in asymptomatic black South Africans, unaware
of their HIV status at the time of blood sampling, while allele 2 appears to be a
modifying factor in patients attending an infectious disease clinic highlights the
complexity of host genetics in the African context. We conclude that multiple lowpenetrance host alleles determine susceptibility to HIV/AIDS and that risk factors
may vary between groups with different genetic backgrounds as a consequence
of gene-gene and/or gene-environment interaction.
Presenting author: DEON PRETORIUS, HUMAN GENETICS, FACULTY OF
HEALTH SCIENCES, UNIVERSITY OF STELLENBOSCH, P0 BOX 19063,
TYGERBERG, CAPE TOWN, South Africa, Tel.: [phone], Fax: [phone], E-mail: [email protected]

WePeA5769 Tumor Necrosis Factor alpha (TNFo), A genetic
mechanism for HIV disease progression?
A.J. Handley, C. Bennett, RP.U. Cameron. University of Melbourne, c/o
Microbiology and Immunology, The University of Melbourne, Parkville. 3052,
Australia
Background: Host genetic markers that protect from HIV infection, increase disease progression or slow progression by rate of CD4 T cell decline have been
associated with Human Leucocyte Antigen (HLA) haplotypes.The effect of a variant in the TNF gene located in the gene dense central HLA region between Class
I and II and HIV disease progression was studied, as this gene has been associated with disease susceptibility or disease progression in other infectious and
autoimmune diseases.
Methods: A retrospective cohort study was undertaken to determine if the gene
variant of TNF (position 308) had an effect of HIV disease progression. Individuals were typed for the variant allele and follow-up collected. Survival time to onset
of triple antiretroviral therapy was used as the endpoint in the study. Possible confounding effects of age and other HLA haplotypes were included in the analysis.
Results: A cohort of individuals was assembled(n=101). No significant difference
between individuals carrying TNF 1 and TNF 1,2 (variant allele) was observed in
median age, follow-up period, CD4 count at first follow up and at initiation of triple
antiretroviral therapy and proportion of individuals on antiretroviral therapy. Using Survival analysis and Cox Proportional Hazards individuals carrying the TNF
variant had a significantly higher hazard ratio at five years follow up (HR 1.77
P= 0.03). Individuals were 77% more likely to have initiated triple antiretroviral
therapy at five years.
Conclusion: Host genetic markers in HIV infection or disease progression may
be important to acknowledge in population studies in response to interventions for
HIV disease, particularly in therapeutic vaccine and new chemotherapeutic agent
trials. Continued research for genes that mediate effects on disease susceptibility
and progression will identify new targets for immune therapy or protective markers
for vaccine strategies.
Presenting author: Amanda Handley, c/o Microbiology and Immunology, The
University of Melbourne, Parkville. 3052, Australia, Tel.: [phone], Fax:
[phone], E-mail: a.handley@ microbiology.unimelb.edu.au
WePeA5770 Role of CCR5-A32, CCR2-641 and SDF1-3'A alleles
in a population of HIV-1 patients with known date
of seroconversion
S. Corvasce', R. Mazzucchellil, A. Cozzi-Lepri2, G. Rezza3, C. Fiorini4,
M.A. Ursitti5, G. Ippolito6, M. Moroni', C. Balotta1. 'Institute of Infectious and
Tropical Diseases - University of Milan, Institute of Infectious and Tropical
Diseases, University of Milan, 'L. Sacco' Hospital, via G. B. Grassi, 74 - 20157
milan, Italy; 2Royal Free and University College - Medical School, London, United
Kingdom; 1stituto Superiore di Sanita, Roma, Italy; 41stituto di Malattie Infettive -
University of Bologna, Bologna, Italy; 5Divisione di Malattie Infettive - 'Santa
Maria Nuova' Hospital, Reggio Emilia, Italy; 61RCCS 'L. Spallanzani, Rome, Italy
Background: CCR5-A32, CCR2-641 and SDF1-3'A alleles may affect HIV-1 disease progression, both alone or in combination. The epidemiological studies performed up to date in seroprevalent HIV-1 populations failed to unequivocally identify a correlation between specific CCR5, CCR2 and SDF-1 genotypes and different rates of progression. In a group of HIV-1 patients with known seroconversion
date, we analysed the prevalence of A32, 641 and 3'A alleles, and estimated the
disease progression in subjects with different genotypes.
Methods: We studied 800 HIV-1 patients with known seroconversion date, belonging to the Italian Cohort Naive Antiretrovirals (I.Co.N.A.; n=324) and the Italian Seroconversion Study (I.S.S.) cohort (n=476). A32, 641 and 3'A alleles were
detected by specific discrimination assays using TaqMan~ chemistry. Survival
analyses were performed by Kaplan-Meier model using CD4 cell counts <200
cells/RL, the initiation of a highly active antiretroviral therapy, the AIDS onset and
the death as end-points.
Results: A32, 641 and 3'A alleles were equally represented in I.Co.N.A. and I.SS.
cohorts and their frequency in the total population was 0.068, 0.122 and 0.251, respectively. The study of long-term nonprogressors in our case-file (n=36) showed
that only the A32 allele was more frequent in this group than in progressors (0.125
vs 0.065; p=0.04). In survival analyses, the CCR5-+/A32 subjects showed a 0.68
relative hazard of disease progression compared to -+/+ (p=.006). Age of patients
and viremia levels did not affect this result. No effect was seen regarding 641 and
3'A alleles.
Conclusions: Our data indicate that CCR5-A32 is the only allele that may play
a major role in delay HIV-1 disease progression. The Cox multivariate analysis
showed no additional effect of 641 allele in our population. In agreement with previous data, the putative role of the 3'A allele was not confirmed in our study.
Presenting author: Stefano Corvasce, Institute of Infectious and Tropical Diseases, University of Milan, 'L. Sacco' Hospital, via G. B. Grassi, 74 - 20157 milan,

Italy, Tel.: [phone], Fax: [phone], E-mail: stefano.corvasce
@unimi.it