CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

levels using cubic spline linear models to flexibly fit the relationship between expression and time. We used linear regression to determine associations between gene expression changes <90 days after infection with HIV-1 RNA set point and CD4/CD8 ratios >1 year after infection. Ingenuity pathway analysis identified gene sets. P-values were adjusted for multiple testing by controlling the false discovery rate (FDR). Results: Expression of 1808 genes changed after HIV-1 infection (FDR<5%). Of these, the maximum expected fold-change during follow-up was 1.4-2 for 408 genes, and >2 for 35 genes. Within 90 days after HIV-1 infection, expression of 7 genes involved in T-cell receptor signaling (e.g. CD8a and CD8b) increased nearly 2-fold versus pre-infection levels before subsequently declining (p=0.03)(Figure 1a). Expression of 28 genes involved in the Type I interferon (IFN) pathway (e.g., IFI27, IFI44, MX1, Tetherin, OAS1/2) increased rapidly <90 days after infection and remained elevated throughout follow-up (p=9.7x10 -10 ,FDR<5%)(Figure 1b). IFI27 expression increased most with a 4-fold increase by 90 days after infection (p=0.0007,FDR=2%). Increased expression of genes in the Type I IFN pathway <90 days after infection was associated with increased CD4/CD8 ratios (p=2x10 - 7 ,FDR<5%), but not HIV-1 set point.

Temporal trajectories of representative genes involved in T-cell receptor signaling (A) and Type I inferferon responses (B). Trajectories were determined using cubic spline linear models to allow flexible relationships between time since HIV-1 infection and gene expression changes. Post-infection gene expression values were evaluated relative to pre- infection values to allow analysis of within-person changes in gene expression. Conclusions: Similar to rhesus macaques, Type I IFN stimulated genes are persistently expressed during early HIV-1 infection. Expression of these genes is associated with CD4/ CD8 ratio but not HIV-1 set point. Further research is needed to identify mechanisms for how ISG expression may alter clinical outcomes. 293 Refinement of Association Signals Assessment of Residual Heritability in Host Control of HIV Viral Load Paul J. McLaren; Istvan Bartha ; Jacques Fellay École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Background: Genome-wide association studies of HIV outcome consistently identify the MHC region as the major genetic influence on disease progression. Through establishment of the International Collaboration for the Genomics of HIV we sought to bring together all existing GWAS data in HIV patients to maximize power to uncover further association signals. Methods: Genome-wide SNP data were collected from 25 clinical centers. Plasma viral load measurements obtained during the chronic phase of untreated infection were available for 6,315 individuals of European ancestry. Missing genotypes were imputed using the 1,000 Genomes Project reference. Single marker association testing was performed per study using linear regression and combined across studies by meta-analysis. Classical HLA alleles and amino acid variants were imputed using the SNP2HLA pipeline. Heritability estimates were calculated using GCTA. Results: Consistent with previous studies, the top association signal was amino acid position 97 in HLA-B (p=4e-143), with independent associations at positions 67 (p=4e-112) and 45 (p=8e-49) in HLA-B and positions 77 (p=2e-12) and 95 (p=4e-5) in HLA-A. All 5 amino acid positions are located in the peptide-binding groove. Controlling for these positions fully accounted for classical class I HLA allele associations. Independent of the MHC, a second peak of association in the CCR5 region (top SNP rs4317138 p=8e-19) was observed. Conditioning out the known effect of CCR5 Δ 32, 57 SNPs remained associated at genome-wide significance (p<5e-8) suggesting multiple additional causal variants in this region. Considering all SNPs and assuming an additive genetic model, we obtained a narrow-sense heritability (h2) estimate of 26% (p<2e-16) for viral load. Removing the HLA and CCR5 regions, we observed a reduced, yet still significant h2 estimate of 16% (p=5e-8). Conclusions: By combining available GWAS data in HIV infected individuals we refined the known association signals in HLA class I and CCR5. Controlling for these main effects, we uncovered additional, independent associations in known regions. Heritability analysis suggested that variation outside known regions, captured through common SNPs, also contribute to HIV control.

Poster Abstracts

243

CROI 2015