CROI 2015 Program and Abstracts

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Poster Abstracts

cytokines following stimulation. Proteomic analysis similarly identified several immune response proteins to be differentially expressed between HIV-stimulated HESN and control explants. Conclusions: Mucosal innate immune reactivity is dampened in HESN subjects as evidenced by absence of pro-inflammatory cytokine production following innate immune stimulation. This may contribute to lower target cell availability leading to lower risk of mucosal HIV transmission in these individuals. Ongoing studies to confirm and characterize these findings will further our understanding of the immunologic events determining HIV susceptibility, thereby providing additional avenues for prevention efforts and microbicide design. 290 Increased Levels of Regulatory T-cells CorrelateWith Protection FromHIV Infection Laura Pattacini 1 ; Jared Baeten 2 ; KatherineThomas 2 ; Tayler Fluharty 1 ; Pamela Murnane 2 ; Deborah Donnell 2 ; Nelly Mugo 2 ; Jairam R. Lingappa 2 ; Connie Celum 2 ; Jennifer Lund 1 1 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, US; 2 University of Washington, Seattle, WA, US Background: An important challenge related to the development of an HIV vaccine is the lack of known correlates of protection from infection. Individuals who remain seronegative despite repeated HIV exposures (HIV-exposed seronegatives, HESN) offer a relevant model in which to identify correlates of protection. One of the proposed mechanisms of protection from HIV infection is overall immune quiescence, potentially in part due to an increased percentage of regulatory T-cells (Tregs). However, the correlation between Treg frequency and HIV acquisition has not been reported which we investigated in a prospective study of serodiscordant couples. Methods: Among a cohort of East African subjects highly exposed to HIV as a result of having an HIV-infected partner, we conducted a nested case-control analysis with 142 individuals, who either acquired HIV during follow-up (cases, n=23) or remained HIV uninfected (controls, n=119), selected for highest exposure based on risk score. Samples tested from the cases were the last available peripheral blood mononuclear cells (PBMCs) before the participant became infected. Controls were tested concurrently with cases and those conducting the testing were blinded as to case status. Tregs were identified as CD3+ CD4+ CD25hi CD127lo FoxP3+ cells. Tregs were further characterized by examination of the activation markers CD39, CTLA-4 and ICOS. The frequency of resting and activated Tregs was determined by CD45RA and CD25 expression. Results: We detected a significantly higher frequency of Tregs in controls, where the average percentage of Tregs among CD3+ T-cells was 3.6%, compared to cases, with 3.1% Tregs (p=0.04). We found no difference in the frequency of resting Tregs (CD45RA+ FoxP3lo), that was 35.2% in controls and 35.0 % in cases (p=0.95) and of activated Tregs, with 4.9% in controls and 5.2% in cases being CD45RA- FoxP3hi (p=0.69). Furthermore, we did not observe any difference in the frequencies of Tregs expressing high levels of the activation markers CD39, CTLA4 and ICOS. Conclusions: This is the first study to demonstrate a lower Treg frequency in subjects who subsequently seroconverted. Our results support a hypothesis that Tregs could play a protective role against HIV infection. Background: Viral load setpoint is a major correlate of HIV disease progression. Genome-wide association studies have identified common human polymorphisms that together explain no more than 15% of its phenotypic variance. Concurrently, studies of the impact of HIV genetic diversity on viral load have produced highly variable estimates. Here we present a joint assessment of the respective contributions of human and viral variation to HIV viral load at setpoint. Methods: Human genotype data across the Major Histocompatibility Complex (MHC) region, full-length consensus HIV sequences and setpoint viral load results were available for 1034 treatment naïve individuals of European ancestry, infected with HIV-1 subtype B. Heritability (h 2 ) estimation was carried out with GCTA using three kernel matrices representing: 1) the human Genetic Relatedness Matrix (GRM) derived from the MHC, 2) the viral GRM derived from the full-length sequences, and 3) the sample-specific noise. The human GRM was estimated from 27 common polymorphisms shown to strongly influence viral load selected by LASSO. Bootstrapped phylogenetic trees were inferred from the viral sequences using RAxML. The viral GRM was derived from the phylogenetic trees by taking the branch length of the shared ancestry (i.e. the distance from the root to the most recent common ancestor). The estimates were repeated on 30 bootstrap trees and 15 bootstrap replicates of the samples. Clinical site was included as a covariates in the analyses. Results: Estimating the host heritability of HIV viral load using the host GRM alone yielded a median estimate of h 2 =8%with an interquartile range (IQR) of 1% across 15 bootstrap replicates of the samples. The estimates of the viral heritability drawn from 30 bootstrapped viral trees had a median of 29% (IQR=10%). Combining both the host and viral relatedness matrices showed a comparable viral heritability of 26% (IQR=9%) but a decreased host contribution of 4% (IQR=0%). Conclusions: This is the first estimate of the combined and respective contributions of the host and the viral genomes to the observed variability of HIV viral load. We showed that both the pathogen and host genomes have detectable impacts on the clinical outcome of infection, which are however not independent. These results suggest that the main predictor of clinical outcome is the viral genotype and that host determination of viral load is largely dependent on its ability to select viral variants. 292 Host Gene Expression Profiles and HIV-1 Infection Outcomes Romel D. Mackelprang 1 ; Ali Filali 2 ; Mark Cameron 2 ; Rafick P. Sekaly 2 ; Elly Katabira 3 ; Allan Ronald 4 ; Glenda Gray 5 ; Connie Celum 1 ; M Juliana McElrath 5 ; Jairam R. Lingappa 1 1 University of Washington, Seattle, WA, US; 2 Case Western Reserve University, Cleveland, OH, US; 3 Makerere University College of Health Sciences, Kampala, Uganda; 4 University of Manitoba, Winnipeg, Canada; 5 Fred Hutchinson Cancer Research Center, Seattle, WA, US Background: HIV-1 infection elicits host gene expression changes that may impact clinical outcomes. Non-human primate studies suggest that early and persistent expression of interferon-stimulated genes differentiate poor outcomes of SIV infection in rhesus macaques from less severe outcomes in sooty mangabeys. We assessed host gene expression in African HIV-1 seroconverters before HIV-1 acquisition through chronic infection to determine if early changes in gene expression associate with subsequent HIV-1 plasma RNA levels and CD4/CD8 ratios. Methods: Genome-wide gene expression microarrays were performed on 78 whole blood samples from 17 African HIV-1 seroconverters, including 14 pre and 64 post-infection samples (up to 450 days post-infection) collected from HIV-1 serodiscordant heterosexual couples. For each gene, we evaluated expression changes relative to pre-infection TUESDAY, FEBRUARY 24, 2015 Session P-C6 Poster Session Poster Hall 2:30 pm– 4:00 pm Host Factors in HIV Pathogenesis 291 Estimating the Respective Contributions of Human and Viral Genetic Variation to HIV Control István Bartha 1 ; Paul J. McLaren 1 ; Chanson J. Brumme 2 ; Richard Harrigan 2 ; AmalioTelenti 3 ; Jacques Fellay 1 1 École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 2 BC Centre for Excellence in HIV/AIDS, Vancouver, Canada; 3 J. Craig Venter Institute, La Jolla, CA, US

Poster Abstracts

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CROI 2015