CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

294 Genetic and Clinical Predictors of CD4 Recovery During Suppressive cART: WIHS Ruth M. Greenblatt 1 ; Kord Kober 1 ; Peter Bacchetti 1 ; Ross Boylan 1 ; Kathryn Anastos 2 ; Mardge Cohen 5 ; Mary A.Young 3 ; Deborah Gustafson 4 ; Bradley Aouizerat 1 On behalf of theWIHS 1 University of California San Francisco, San Francisco, CA, US; 2 Montefiore Medical Center, University Hospital for Albert Einstein College of Medicine, New York, NY, US; 3 Georgetown University, Washington, DC, US; 4 State University of New York, Downstate, Brooklyn, NY, US; 5 CORE Center, Chicago, IL, US; 6 National Institutes of Health (NIH), Bethesda, MD, US Background: Blood CD4 cell counts fail to recover in a significant minority of virologically suppressed cART recipients. We hypothesized that host genetics, including novel mutations, and key clinical characteristics would predict rapid versus slow recovery in women with HIV RNA levels below detection during cART. Methods: Longitudinal treatment response and clinical data were generated by the WIHS cohort, and used to define rapid vs. slow CD4 cell recovery among women during, at a minimum, the first 2.5 years of cART with virologic suppression. Whole exome sequencing (WES) was conducted on 95 women, with the most consistently slow (n=47) or rapid (n=48) CD4 recoveries. Additive stepwise logistic regression identified statistically significant predictors of rapid recovery. Results: Each decade increase in age at the start of viral suppression while on cART reduced the odds ratio (OR) of rapid recovery by 0.50 (95% CI 0.27-0.92). Self-reported adherence ≥ 95% increased the OR of rapid recovery by 2.7 (CI 1.04-7.0). When added as a third predictor, higher CD4 nadir approached statistical significance (OR 1.34 per 100 cells, CI 0.96-1.87). Following WES analysis, rapid CD4 recovery was statistically significantly associated with sequence anomalies aggregated at the gene level for 68 genes (all p<0.001). Notably, the host genes identified were enriched for genes (n=14; 20.6%) that encode for proteins that interact with HIV-encoded proteins. An additional 38 genes (55.9%) encode for proteins that in turn interact with other host proteins known to interact with HIV-encoded proteins. Conclusions: Despite consistent viral loads below detection on cART, self-reported nonadherence and higher age adversely influenced CD4 recovery. The finding that nonadherence and polymorphisms of HIV target genes influence CD4 recovery suggest that intermittent or low grade viral replication contributed to slow CD4 response in this sample of cART recipients with ≥ 2.5 years of virologic suppression. 295 Host Genetic Predictors of Plasma Kynurenine/Tryptophan Among Treated HIV+ Ugandans Sulggi A. Lee 1 ; Joel Mefford 1 ;Yong Huang 1 ; John S.Witte 1 ; Jeffrey Martin 1 ; David R. Bangsberg 2 ;Taisei Mushiroda 3 ; Michiaki Kubo 3 ; Deanna Kroetz 1 ; PeterW. Hunt 1 1 University of California San Francisco, San Francisco, CA, US; 2 Massachusetts General Hospital and Harvard University, Boston, MA, US; 3 RIKEN Center for Genomic Medicine, Wako, Japan Background: Indoleamine 2,3-dioxygenase-1 (IDO) activity, as assessed by plasma kynurenine/tryptophan (KT) ratio, is induced by immune activation and microbial translocation, causes T cell proliferative defects and Th17 depletion, and strongly predicts mortality in treated HIV infection. Whether host genetic variation contributes to IDO activity is unknown. Methods: We assessed common genetic polymorphisms in association with plasma KT ratio in HIV-infected Ugandans in the UARTO and ARKS cohorts at months 6 and 12 of confirmed antiretroviral therapy (ART)-mediated viral suppression using genome (Illumina OmniExpress) and exome (Affymetrix Axiom) array genotyping. Linear mixed models adjusted for cohort, gender, pregnancy status, and population ancestry were employed for candidate gene and discovery-based analyses. Genome-wide imputation was performed using the 1000 Genomes reference panel. For the candidate gene analysis, genes encoding known factors that induce IDO were included. Results: Participants (N=597) were mostly female (62%) with a median age of 35, and had advanced disease (median pre-ART CD4+ count 135 cells/mm 3 and HIV RNA 5.1 log 10 copies/mL). For the candidate gene analysis, single nucleotide polymorphisms (SNPs) in TNF (rs17200810 a , rs34451538, rs114064880, rs11575838), IFNGR1 (rs276565 a ), and TLR4 (rs2770148 b ) genes were significant at Bonferroni P <5E10-5. For the GWAS analysis, one intergenic SNP (between CSPG5 and ELP6 ) achieved genomewide significance (rs56185965, P =8.7E-09), while several other SNPs achieved near-genomewide significance at P <5E10-7, including genes encoding 2 different protein tyrosine phosphatases involved in reversible phosphorylation during cell signaling, PTPRM (rs75257475 b , rs115059620) and PTPRN2 (rs6950107), as well as a SNP downstream of CYP24A1 (rs13041834 b ), which encodes an enzyme that plays a major role in vitamin D metabolism and lies in an H3K27Ac histone mark-enriched region. Conclusions: Our candidate gene analysis suggests that host genetic variation may modify the impact of IFN-g, TNF-a, and microbial products (via toll-like receptor 4) on IDO induction. The GWAS analysis also identified potential novel mechanisms by which host genetics may modify IDO induction via protein tyrosine phosphatase or vitamin D pathways. Additional studies are needed to confirm these findings in other populations and to validate their functional impact on IDO induction. a Genotyped SNP; b In linkage disequilibrium (LD) with a genotyped SNP 296 Regulation of IL-32 Expression by a Promoter Polymorphism and MicroRNA29b in HIV-1 Patients Carolina Scagnolari ; Giulia Cacciotti; Carla Selvaggi; Noemi Giustini; Ivano Mezzaroma; Massimo Gentile; Gabriella D’Ettorre; OmbrettaTurrziani;VincenzoVullo; Guido Antonelli Sapienza University of Rome, Rome, Italy Background: Interleukin-32 (IL-32) is a multi-isoform cytokine that has recently received growing attention as a key component in the antiviral immune response to HIV-1 infection. We previously demonstrated that IL-32 isoforms are highly expressed during HIV-1 infection and that it is associated with low levels of viremia and can increase the expression of well-established type I IFN induced mixovirus resistance proteins A (MxA). Now, we evaluated whether changes in miRNA-29b levels, which has been shown to target the IL-32 mRNA 3’-untranslated region, and a promoter polymorphism in the IL-32 gene, influence IL-32 isoforms and indirectly MxA expression in untreated HIV-1 infected patients Methods: PBMC samples from 104 untreated HIV-1 infected patients (male/female 82/22; median age: 40 years; median viral load: 46580 HIV-RNA copies/ml and median CD4+T cell count: 355 cells/mm 3 ) were collected at the Sapienza University Hospital (Rome, Italy). Levels of IL-32 isoforms ( α and non α ) mRNA, MxA-mRNA, microRNA29b and rs28372698 (T/A) IL-32 promoter s ingle nucleotide polymorphisms (SNPs) were evaluated by using distinct TaqMan assays. Results: The IL-32 rs28372698 (T/A) genotype frequency was TT (26 %), AT (53%) and AA (21%) among untreated HIV-1 infected patients. We found that patients carrying AA IL-32 genotype have higher expression of IL-32 isoforms ( α and non α ) and MxA than those with AT or TT IL-32 genotypes concomitantly with a twofold decrease on HIV-1 viral load. No differences in terms of CD4+ T cell counts were recorded among HIV-1 infected patients carrying different IL-32 genotypes. Furthermore, an inverse correlation between miR-29b and IL-32non α levels was observed in HIV positive patients ( p<0.05 ; r =-0.27) while no significant correlation was found with IL-32 α levels. Lastly we found that a strong positive correlation between IL-32non α and MxA transcript levels exists ( p <0.001; r =0.58) and that patients expressing higher levels of miR-29b showed lower levels of MxA ( p <0.01; r =-0.41). Conclusions: Our results indicate that the expression of anti HIV-1 IL-32 isoforms are influenced both by the presence of IL32 promoter polymorphism and levels of miRNA-29b, highlighting the importance of host genetic factors and cellular microRNA in the regulation of IL-32 during HIV-1 patients.

Poster Abstracts

244

CROI 2015