CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Methods: CD4+ T cells were obtained before, during, and after panobinostat administration (n=15). For nine of the participants, LPMCs were collected during and after panobinostat treatment. Additionally, plasma samples were collected during an ATI for nine of the trial participants. Five participants participated in both the ATI and collection of LPMCs. We used single-proviral/genome sequencing to determine the genetic composition HIV-1 DNA and RNA. Phylogenetic analyses were conducted using MEGA 6.0. Results: We identified an expansion of clonal cell-associated HIV-1 DNA in the peripheral blood, which is indicative of previous cellular proliferation, that matched viral RNA sequences from the ATI. Cell-associated HIV-1 DNA sequences from CD4+ T cells from both blood and LPMCs were closely related to HIV-1 RNA sequences detected in plasma during the ATI (>99% similarity; blood n=38 sequences, LPMC n=12 sequences). Furthermore, we identified cell-associated HIV-1 RNA sequences in CD4+ T cells from blood and LPMCs collected during panobinostat treatment that were closely related to plasma sequences from the ATI (>99% similarity; blood n=6 sequences LPMC: n=1 sequence). Conclusions: Clonally expanded HIV-1 is capable of contributing to viremia, indicating that replication-competent virus is maintained in proliferating cells. Importantly, we found that cell-associated HIV-1 DNA in the peripheral blood CD4+ T cells and LPMCs both contribute to plasma viremia following discontinuation of ART. Furthermore, HIV-1 RNA from virus that later emerged during ATI was expressed in the blood and LPMCs during panobinostat treatment. Thus, both of these important compartments of latent virus should be prioritised in remission and curative strategies. 349 HIV DNA Set Point Remains Elevated in Untreated vs Treated Acutely Infected Thais Jintanat Ananworanich 1 ; Nicolas Chomont 2 ; Leigh . Eller 3 ; Eugène Kroon 4 ; Meera Bose 3 ; Marty Nau 3 ; Suteeraporn Pinyakorn 3 ; Nelson L. Michael 5 ; Nittaya Phanuphak 4 ; Merlin L. Robb 3 ; for the RV254/SEARCH010 Study Groups 1 Military HIV Rsr Prog, Bethesda, MD, USA; 2 Univ de Montréal, Montreal, QC, Canada; 3 US Military HIV Rsr Prog, Walter Reed Army Inst of Rsr, Silver Spring, MD, USA; 4 SEARCH, Bangkok, Thailand; 5 US Military HIV Rsr Prog, Bethesda, MD, USA Background: The dynamics of HIV reservoir seeding in early acute HIV infection (AHI) and the longitudinal comparison of reservoir markers in antiretroviral therapy (ART) untreated and treated AHI is poorly understood. Methods: Total and integrated HIV DNA were measured in the peripheral blood mononuclear cells (PBMCs) from two prospective AHI protocols of untreated (RV217, n=12) and treated (RV254, n=71) Thais. HIV DNA levels were log 10 transformed prior to analysis. Differences between groups were assessed using two-tailed Student’s t test. Results: The untreated cohort was younger (median age 23 vs. 29 years in the treated cohort). The distribution of Fiebig stages were similar: untreated: 7 (58%) FI/II and 5 (42%) FIII/IV; treated: 33 (46%) FI/II and 38 (54%) FIII/IV. Baseline HIV RNA was higher in those untreated (6.4 vs. 5.7 log 10 copies/ml in treated, p=0.04). Mean time to ART initiation was 2 10 copies/10 6 PBMC, p=0.006). After ART, the treated cohort had a marked reduction in total and integrated HIV DNA levels whereas these changed little in those untreated. The mean values at week 48 for total HIV DNA were 2.6 vs. 0.9 log 10 copies/10 6 PBMC and integrated HIV DNA were 1.5 vs. 0.1 log 10 copies/10 6 PBMC for the untreated and treated cohorts, respectively. The mean differences of total HIV DNA between the untreated vs. treated cohorts increased from 1 log 10 copies/10 6 PBMC at baseline to 1.7 log 10 copies/10 6 PBMC at week 48 (p<0.0001) and 2.3 log 10 copies/10 6 PBMC at week 144 (p <0.0001). Similarly, the mean differences of integrated HIV DNA between the untreated vs. treated cohorts increased from 0.9 log 10 copies/10 6 PBMC at baseline to 1.4 log 10 copies/10 6 PBMC at week 48 (p<0.0001) and 1.9 log 10 copies/10 6 PBMC at week 144 (p <0.0001). The total and integrated HIV DNA differences between cohorts remained after adjusting for baseline HIV DNA values. Conclusions: Levels of HIV DNA “set point” appears to be established early during Fiebig I-IV AHI and determines the reservoir size in chronic infection. Over three years without ART, persons with AHI have HIV DNA that is 2 logs higher than those on ART. The window of opportunity to significantly alter HIV DNA levels with ART is possibly very early. days from enrollment in the treated cohort. Geometric mean total HIV DNA over time is shown in the figure. Mean baseline values were higher in the untreated vs. treated cohorts for total DNA (2.8 log vs. 1.8 log 10 copies/10 6 PBMC, p=0.02) and integrated DNA (1.6 vs. 0.7 log

Poster Abstracts

350 Impact of Long-term Antiretroviral Therapy (ART) on Cellular HIV and Inflammation

Rajesh T. Gandhi 1 ; Deborah McMahon 2 ; Ronald Bosch 3 ; Christina Lalama 3 ; Josh Cyktor 2 ; Bernard J. Macatangay 4 ; Charles Rinaldo 2 ; Ann Collier 5 ; Joseph J. Eron 6 ; JohnW. Mellors 2 1 Massachusetts General Hosp, Boston, MA, USA; 2 Univ of Pittsburgh, Pittsburgh, PA, USA; 3 Harvard Sch of PH, Boston, MA, USA; 4 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA; 5 Univ of Washington, Seattle, WA, USA; 6 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: The longitudinal impact of ART on markers of HIV persistence and inflammation is incompletely understood. Methods: Participants with chronic HIV who initiated ART in ACTG trials had pre- and on-ART samples tested for cell-associated HIV RNA and DNA (CA-RNA, CA-DNA), plasma HIV RNA, IL-6, hsCRP, sCD14, sCD163. Results: 101 participants with median duration of virologic suppression on ART of 7 yrs (range 4-15) were analyzed. Prior to ART, higher CA-DNA correlated with higher CA-RNA (r=0.67, p<0.001) and lower CD4 count (r=-0.51, p<0.001). After 4 yrs of ART, CA-DNA fell 15-fold whereas CA-RNA dropped 525-fold (Figure). Slope of CA-DNA decay was greatest during the first 4 yrs but DNA continued to decline slowly thereafter (5%/yr decline, p=0.002; 69% had negative slope). By contrast, after yr 1 there was no further decline in CA-RNA. Despite suppression of plasma viremia, participants with high CA-DNA before ART continued to have high DNA while on ART (r≥0.61, p<0.001). Other factors associated with high on-ART CA-DNA included low pre-ART CD4 count and low on-ART CD4:CD8 ratio (eg, at yr 1 of ART, r=-0.44, p<0.001). The correlation between CA-DNA and CA-RNA persisted at all time points (r=0.51-0.57, all p<0.001) but only DNA correlated with plasma RNA by single-copy assay (r=0.32, p=0.013; assessed at yr 4). IL-6 and sCD163 dropped significantly during the first yr of ART and then stabilized; sCD14 and hsCRP did not decline after ART. No consistent correlations were found between CA-DNA or CA-RNA and inflammatory biomarkers at pre- or on-ART time points.

133

CROI 2016