CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

376 Stable Total HIV-1 DNA Levels Prior and Post ART Interruption in Chronic HIV Emmanouil Papasavvas 1 ; Matthew Strain 2 ; Steven Lada 2 ; Jocelin Joseph 1 ; Livio Azzoni 1 ; KaramMounzer 3 ; Jay R. Kostman 4 ; Douglas D. Richman 2 ; Luis J. Montaner 1 1 The Wistar Institute, Philadelphia, PA, US; 2 VA San Diego Healthcare System and the University of California, San Diego, CA, US; 3 Jonathan Lax Immune Disorders Treatment Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA, US; 4 Presbyterian Hospital–University of Pennsylvania Hospital, Philadelphia, PA, US Background: The persistence of the HIV reservoir during antiretroviral therapy (ART) is a barrier to HIV eradication. The impact of viremic episodes on cell-associated HIV DNA or RNA in the context of ART-mediated suppression remains unknown. Methods: Peripheral blood mononuclear cells (PBMC) from 23 ART-suppressed, chronically HIV-1-infected subjects were evaluated at initiation of treatment interruption (TI, baseline), during HIV viremia soon after TI, and following ART-mediated HIV viral load (VL) re-suppression for: a) T cell activation [CD38, HLA-DR, CD28, CD95 and TNFRII expression on CD4 + or CD8 + T cells] by flow cytometry, and b) viral measures including: i) cell associated HIV DNA [total HIV DNA (pol copies) and episomal 2-long terminal repeat (2-LTR) circles] by droplet digital PCR (ddPCR), and ii) cell associated HIV unspliced (gag), multi spliced RNA (tat/rev) and poly-A tailed transcripts (PolyA), by reverse transcriptase-ddPCR. Differences between time points were tested using Wilcoxon Signed-Rank or paired t-tests. Correlations were assessed using Spearman tests. All statistics used JMP Pro11. Results: The median HIV VL during TI [median time=4 weeks, interquartile range (IQR)=4-9] was 72900 copies/ml (IQR=32558-127193). When compared to pre-TI levels, TI resulted in a decrease in CD4 + T cells/mm 3 (p<0.0001), increase in T cell activation [e.g. CD8 + CD38 + percent p=0.0005], and increase in cell associated HIV DNA (pol p<0.0001, 2-LTR p=0.0362) and RNA (gag p<0.0001, tat/rev p<0.0001, PolyA p<0.0001). Upon resumption of ART, HIV re-suppression occurred after a median of 16 weeks (IQR=12-22) and resulted in restoration of CD4 + T cells/mm 3 , reduction of T cell activation, and return of total HIV DNA and cell-associated HIV RNA to pre-TI levels. However, levels of activated (e.g. HLA-DR + ) CD4 + T cells and 2-LTR circles remained higher than pre-TI levels (p=0.0171 and p=0.0323, respectively) even after viral re-suppression. Pre-TI mean fluorescent intensity of CD38 on CD4 + HLA-DR + T cells was positively associated with total HIV DNA levels observed during TI (p=0.034, Rho=0.4437) and after viral re-suppression (p=0.0289, Rho=0.4658). Conclusions: ART-mediated HIV VL re-suppression restored total HIV DNA to pre-TI levels, but retained higher 2-LTR levels. In addition, pre-TI T cell activation levels were positively correlated with total HIV DNA levels observed during TI and following viral re-suppression. 377 Aviremia 10-Year Post-ART Discontinuation Initiated at Seroconversion Sabine I. Kinloch 1 ; Lucy Dorrell 2 ; HongbingYang 2 ; LinosVandekerckhove 3 ;Ward de Spiegelaere 3 ; Eva Malatinkova 3 ; SabineYerly 4 ; DanielWebster 5 ; Margaret Johnson 5 1 University College London, London, United Kingdom; 2 University of Oxford, Oxford, United Kingdom; 3 Universitair Ziehenhuis Gent, Gent, Belgium; 4 Geneva University Hospital, Geneva, Switzerland; 5 Royal Free London NHS Foundation Trust, London, United Kingdom Background: Early ART initiation is associated with impact on HIV-1 reservoir establishment and decay with the potential for virological control post-treatment discontinuation. Underlying mechanisms of post-virological control remain unclear. Methods: We report on a clade C-infected female patient who has maintained undetectable viremia for 10 years after stopping a 6-year treatment period initiated at PHI with initial virological failure while on ART and describe her virological parameters and HIV-1 specific T cell responses. Results: A 23-year-old female seroconverted with a 3-week long severe acute retroviral syndrome in October 1997. Baseline characteristics and follow-up viral load (VL) and CD4 T cells data are shown on Figure. Compromised viro-immunological parameters with CD4 <200 cells/mm 3 on 3 occasions and VL >750,000 HIV-1 copies(c)/mL (clade C) were present before ART initiation on 20.10.97 (AZT-3TC-indinavir 800 mg tds switched to ritonavir 600 mg bd 2 weeks later). Failure of this regimen up to 94,000 c/mL prompted treatment intensification and aviremia was achieved in April 1999. ART was maintained until January 2004 followed by aviremia for 10 years with preservation of CD4 T cells and CD4/CD8 ratio>1 (Figure). HLA genotype was not one generally associated with a favorable outcome. At 10 years of aviremia (2014), total HIV-1 DNA, integrated HIV-1 DNA and 2-LTR circles were 148.93 (95% CI: 76.99 - 229.64), 134.31 (95% CI: 56.47 – 304.39) and 3.89 (95% CI: 0 - 9.15) HIV-1 copies/million PBMCs, respectively. CD4 and CD8 HIV-1 specific T cell responses showed moderately potent CD8+ T cell inhibition of a clade-matched HIV-1 isolate equivalent to that which we have observed in ART-naïve chronically infected subjects with VL set-point <10,000 HIV-1 copies/mL. Unusually broad gag-specific IFN- γ CD4 responses were detected, of note, targeting multiple regions of genetic vulnerability that are associated with virological control.

Poster Abstracts

Conclusions: Persistence of intermediate levels of total and integrated HIV-1 DNA and broad HIV-1 gag-specific CD4 T cell responses, together with preserved CD8+ T cell viral inhibitory activity were associated with prolonged aviremia post-stopping treatment, suggesting that further insight into CD4 T cells should be gained in terms of the mechanisms underlying virological control post-ART. 378 Identifying HIV Variants that Rebound after Treatment Interruption Mary F. Kearney 2 ;Wei Shao 3 ; RajeshT. Gandhi 4 ; Brandon F. Keele 3 ; Jonathan Z. Li 1 1 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, US; 2 National Cancer Institute (NCI), Frederick, MD, US; 3 Frederick National Laboratories for Cancer Research, Frederick, MD, US; 4 Massachusetts General Hospital, Harvard Medical School, Boston, MA, US Background: Our knowledge of the source of rebounding HIV after analytic treatment interruption (ATI) is limited. Understanding the origin of HIV variants during early rebound would provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. We examined HIV single-genome sequences (SGS)

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CROI 2015