CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions: The size of the active HIV reservoir, as reflected by levels of CA-RNA and RV, is associated with the time to viral rebound after interrupting ART. CA-RNA and RV have the potential to serve as biomarkers of efficacy for therapies aiming to achieve sustained ART-free HIV remission. 111LB Biomarkers to Predict Viral Rebound at Antiretroviral Therapy Interruption in SPARTAC Jacob Hurst 1 ; JamesWilliams 1 ; John P.Thornhill 2 ; Matthew Pace 1 ; ChrisWillberg 1 ; Elizabeth Hamlyn 3 ; Abdel Babiker 4 ; Rodney Phillips 1 ; Sarah Fidler 2 ; John Frater 1 on behalf of the SPARTACTrial Investigators 1 University of Oxford, Oxford, United Kingdom; 2 St Mary’s Hospital–Imperial College Healthcare NHS Trust, London, United Kingdom; 3 King’s College London, London, United Kingdom; 4 Medical Research Council Clinical Trials Unit, London, United Kingdom Background: Treatment of HIV-1 infection with antiretroviral therapy (ART) in the first few weeks or months following transmission may induce a state of virological remission or ‘post-treatment control’ (PTC), in which viraemia remains suppressed when ART is stopped. We present an analysis of 18 immunological and virological biomarkers measured in primary HIV-1 infection (PHI) to determine if they may help predict PTC after treatment interruption (TI). Methods: We retrospectively analysed a sub-group of samples from SPARTAC - a randomised controlled study of PHI incorporating a TI after 48 weeks of ART. We measured HIV-1 specific CD4 and CD8 T cell ELISpot responses, markers of T cell activation (HLA DR, CD38, CD25, CD69) and exhaustion (Tim-3, Lag-3, PD-1, TIGIT), soluble markers (Il-6, d-dimer), HIV-1 DNA (Total and Integrated), cell-associated unspliced RNA, CD4 count, plasma viral load and the CD4/CD8 ratio. Statistical analyses explored associations between biomarkers and Total HIV-1 DNA and time to viral rebound at TI, with measurements taken, where samples permitted, pre-therapy in all participants and at 48 weeks in those undertaking TI. Results: We analysed 154 individuals prior to starting ART, a median of 73.8 days from the estimated date of seroconversion. 47 participants undertook a TI after 48 weeks of ART. In univariable regression models undertaken with samples from pre-therapy baseline, CD4/CD8 ratio, CD4 count, plasma viral load, CD8 CD38, CD8 PD-1, CD8 HLA DR, CD4 HLA DR, CD8 Lag-3 and d-dimer were significantly associated (all P<0.05) with HIV-1 DNA levels, but only CD4 count, viral load, CD8 CD38, CD8 Lag-3 and d-dimer survived in multivariable analyses. When measured pre-therapy, and adjusting for levels of HIV-1 DNA, T cell exhaustion marker expression on CD4 (PD-1, Tim-3 and Lag-3) and CD8 (Tim-3 only) T cells predicted time to the return of viraemia (n=20; Table 1), but notably not when measured at TI. Apart from Total HIV-1 DNA, in this sub-group analysis we found no evidence for any other biomarkers associating with rebound when measured at baseline or at TI.

Conclusions: In the search for an algorithm of biomarkers to help stratify treated PHI patients according to likelihood of PTC, these data indicate that pre-therapy measurements may be informative and that markers of T cell exhaustion should be included alongside HIV-1 DNA levels. This may also open critical new avenues for understanding the mechanisms underlying PTC, which need to be explored in larger cohorts.

Oral Abstracts

112LB HIV-1 Diversity and Tropism of Rebound Virus After Treatment Discontinuation Maria M. Bednar 1 ; Blake Hauser 1 ; Jeffrey M. Jacobson 2 ; Ian Frank 4 ; Joseph J. Eron 3 ; Ronald Swanstrom 1 On behalf of the NWCS 379 team

1 University of North Carolina, Durham, NC, US; 2 Drexel University College of Medicine, Philadelphia, PA, US; 3 University of North Carolina, Chapel Hill, NC, US; 4 University of Pennsylvania, Philadelphia, PA, US Background: Suppressive antiviral therapy has not been successful in eliminating virus, as patients on suppressive therapy retain a persistent, measurable, stable low-level viremia (LLV), and people discontinuing therapy see a rebound of virus from a persistent reservoir, as seen in the ACTG study A5068. ACTG study A5068 was designed to determine the efficacy of structured treatment interruptions and/or vaccination with an ALVAC-HIV vector for controlling viral replication after therapy discontinuation. Arm A (n=24) received neither STI nor vaccination, virologic rebound was detectable 2-4 weeks after discontinuation of therapy, and reached a peak several weeks later. We have used single genome amplification (SGA) of the viral env gene to assess genetic diversity followed by cloning to examine the tropism of the rebound virus by performing tropism assays to determine if the virus was adapted to grow in T cells (requiring high levels of CD4) or adapted to grow in macrophages (able to enter cells with low levels of CD4). Methods: Viral RNA was isolated from the first available blood plasma sample containing viral load >1000 copies/mL from subjects infected with subtype B HIV-1 who had stopped therapy (10 total). We performed SGA to isolate individual env gene amplicons, 51 of which were cloned (average of 4 amplicons per tree) and infectivity analyzed at varying CD4 levels using Affinofile cells, in order to determine the viral entry phenotype for CD4 usage. Results: Phylogenetic analysis of the viral env genes showed low diversity in each subject, consistent with an initially clonal repopulation of the viral population during rebound. No evidence of macrophage-tropic virus was found meaning that all of the rebound env genes tested encoded proteins that required high levels of CD4 for efficient entry of pseudotyped virus into Affinofile cells. Conclusions: The source of the rebound virus is poorly understood, with the current model assuming this virus comes from resting CD4+ T cells; however, other cell types could be the source of this virus. Our analysis further excludes a myeloid cell source, where virus was persistently infecting these cells prior to therapy. Such a virus would have adapted to be able to use low levels of CD4, and this type of virus was not detected as the rebound virus. While our analysis does not identify the cell type harboring the virus that initiated the rebound, it is consistent with a CD4+ T cell as the source of the virus. 188 HIV-1 Exploits CD169 to Evade IFN α -Induced Antiviral State in Myeloid Cells Hisashi Akiyama 1 ; Nora Ramirez 1 ; Gregory Gibson 2 ; SimonWatkins 2 ; Zandrea Ambrose 2 ; Rahm Gummuluru 1 1 Boston University School of Medicine, Boston, MA, US; 2 University of Pittsburgh School of Medicine, Pittsburgh, PA, US; 3 University of Pittsburgh School of Medicine, Pittsburgh, PA, US Background: A hallmark of HIV-1 infection in vivo is chronic immune activation concomitant with type I interferon (IFN-I) production. Although IFN-Is induce an antiviral state in many cell types, HIV-1 can replicate even in the presence of IFN-Is in vivo. We have recently identified the IFN-I-inducible protein CD169 as an HIV-1 receptor on myeloid dendritic

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CROI 2015