CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

281 SEX-BASED DIFFERENCES IN HIV RESERVOIR ACTIVITY AND RESIDUAL IMMUNE ACTIVATION

Eileen Scully 1 , Monica Gandhi 2 , Rowena Johnston 3 , Rob Gorelick 4 , Jeffrey D. Lifson 5 , Sharon R. Lewin 6 , Jonathan Karn 7 , Nicolas Chomont 8 , Peter Bacchetti 2 , Steven G. Deeks 2 1 The Johns Hopkins Univ, Baltimore, MD, USA, 2 Univ of California San Francisco, San Francisco, CA, USA, 3 amfAR, New York, NY, USA, 4 Leidos Biomed Rsr, Inc, Frederick, MD, USA, 5 Frederick Natl Lab, Frederick, MD, USA, 6 Univ of Melbourne, Melbourne, Australia, 7 Case Western Reserve Univ, Cleveland, OH, USA, 8 Univ de Montréal, Montréal, QC, Canada Background: Plasma HIV RNA levels are lower in women than men in the absence of antiretroviral therapy (ART), particularly in early infection. Less is known about sex differences in HIV during ART. We recently found that estrogen modulates HIV transcription ex vivo. Here, we sought to define sex differences in the size and activity of the HIV reservoir in a cohort of premenopausal women and matched men on ART. Methods: Premenopausal women on ART with ≥1 year of viral suppression were prospectively enrolled (n=26) and matched with men (n=26) on age, duration of viral suppression, CD4 count/nadir and unusual clinical phenotypes. HIV persistence measurements include: integrated HIV DNA (iDNA) in CD4 T cells, residual plasma viremia by single copy assay (SCA) for HIV gag (HMMCgag), and cell associated (CA) multiply spliced (ms) and unspliced (us) HIV RNA in CD4 T cells. The frequency of CD4 T cells producing tat/rev RNA after activation was measured by TILDA in a subset of subjects. T cells were phenotyped by flow cytometry. Virologic data were analyzed by univariate and multivariate negative binomial regression and immune markers were compared with nonparameteric statistics (Mann Whitney). Results: HIV iDNA levels were comparable between men and women (p=0.47), but female sex was associated with a 76% lower level of residual viremia by SCA (p=0.011) in a multivariate model. CA msHIV RNA was also 6-fold lower in women (p=0.002) in a one-predictor model, and 4-fold lower when adjusted for nadir CD4 and controller phenotype (p=0.009). CA usRNA was ~35% lower in women by univariate and multivariate models (p>0.05). The frequency of inducible virus (TILDA: iDNA ratio) was lower in women (Mann- Whitney p=0.019), suggesting a lower inducible reservoir in women. Women demonstrated a lower proportion of HLADR/CD38+ CD4 and CD8 T cells than men (p<0.05) and lower PD-1 expression, most notably in central memory CD8 T cells (p<0.001). Conclusion: In a well-matched cohort of ART-treated, virally suppressed women and men, multiple measures of virus activity and immune activation/exhaustion were lower in women despite comparable frequencies of CD4+ T cells harbouring HIV DNA. These data support sex differences in control of HIV latency. Biologic sex may impact the efficacy of curative interventions and manipulation of sex hormones may play a role in cure strategies. 282 SOLUBLE BIOMARKERS IN ACUTE HIV INFECTION REVEAL INSIGHT INTO HIV RESERVOIR Jeffrey E Teigler 1 , Bonnie Slike 1 , Nicolas Chomont 2 , Eugene Kroon 3 , Merlin L. Robb 1 , Jintanat Ananworanich 1 , Nelson L. Michael 1 , Hendrik Streeck 4 , Shelly J. Krebs 1 , for the RV254/ RV217 Study Groups 1 US Military HIV Rsr Prog, Silver Spring, MD, USA, 2 Univ de Montréal, Montreal, QC, Canada, 3 SEARCH, The Thai Red Cross AIDS Rsr Cntr, Bangkok, Thailand, 4 Inst for HIV Rsr, Essen, Germany Background: Several biomarkers are induced during acute HIV infection, remain elevated during ART, and have been associated with disease progression. However, their role in HIV pathogenesis and reservoir establishment remains unclear. We explored HIV-associated biomarker signatures longitudinally and their relationship with HIV reservoir dynamics following ART initiation. Methods: 82 biomarkers were assessed by Luminex bead technology in Thai individuals at baseline, prior to HIV infection, and during viral upslope (d1-d5), peak viral load (d9-d15), early chronic (~7m-8m) and late chronic (~2y) timepoints following infection in ART-naive (n=13) or individuals who began continuous ART during acute HIV infection (n=40) from the ongoing RV217 and RV254 trials. HIV-1 viral loads (VL) were assessed by HIV RNA in peripheral blood and cell-associated DNA. Results: Distinct biomarker pathways were induced with differential temporal kinetics in HIV acute infection. Proinflammatory markers (e.g. MCP-1, MCP-2) significantly rose during acute infection but resolved by chronic timepoints. TNF-α- and IFN-γ-signaled pathways were induced during peak viremia and persisted in ART-naïve individuals. During acute infection, levels of MIP-3β, sTNFR-II, IP-10, I-TAC, TNF-α, MIG, sTNFR-II, MCP-1, and MCP-2 correlated positively HIV VL (p<0.01, all). In individuals given ART during acute infection, rate of HIV RNA decline in plasma was correlated with levels of MIP-3β (r = -0.318; p=0.04), I-TAC (r=-0.354; p=0.03), and IP-10 (r=-0.322; p=0.04) prior to ART initiation. Levels of cell-associated HIV DNA at week 96 post treatment initiation correlated with levels of sTNFR-II (r=0.407; p=0.04) prior to ART. HIV-associated biomarkers TNF-α, sTNFR-I, sTNFR-II, IP-10, MIG, and I-TAC remained elevated at chronic infection during treatment relative to HIV-uninfected individuals (p<0.05, all), indicating biomarkers associated with HIV VL remain elevated in the absence of detectable virus in circulation. Conclusion: A comprehensive analysis of biomarkers induced in HIV infection reveal viral-associated factors that remain elevated despite successful ART. Levels of these markers correlate with rate of viral decline after treatment and with levels of viral reservoir two years following infection. The use of these markers to better inform treatment interruption and immune therapies remains under study.

Poster and Themed Discussion Abstracts

CROI 2017 111