CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

359 THE THERAPEUTIC VACCINE VACC-4X TARGETS GAG CTL EPITOPES WITH PREEXISTING MUTATIONS Anni Winckelmann 1 , Vincent Morcilla 2 , Wei Shao 3 , Lars Østergaard 1 , Ole S. Søgaard 1 , Martin Tolstrup 1 , Sarah Palmer 2 1 Aarhus University Hospital, Aarhus, Denmark, 2 The Westmead Institute for Medical Research, Westmead, NSW, Australia, 3 Frederick National Laboratory for Cancer Research, Frederick, MD, USA Background: Therapeutic HIV immunisation followed by latency reversal has been suggested as a strategy to achieve a functional cure for HIV. The efficacy of a therapeutic peptide vaccine to improve antiviral immune responses will depend on the presence of potential escape mutations in the target regions. Here we investigate the HIV phylogenetic composition of the four regions targeted by the therapeutic vaccine Vacc-4x in participants in a clinical vaccine trial. Methods: In a clinical trial, 17 participants on suppressive ART were vaccinated with six doses of the therapeutic HIV gag peptide vaccine Vacc-4x (Bionor Pharma) over 12 weeks, then three doses of romidepsin over three weeks followed by an analytical treatment interruption (ATI). Seven participants were selected for sequencing analysis. We performed single-genome/proviral sequencing of a 2.1 kb region spanning the p24-RT region on HIV-1 DNA and cell-associated RNA from peripheral CD4+ T cells from a total of six time points during the trial, as well as plasma HIV-1 RNA from the ATI. We analyzed HLA-specific CTL epitopes in the four regions targeted by Vacc-4x using the Los Alamos epitope and variant databases. CD8+ immune responses were assessed by intracellular cytokine staining and viral inhibition assays. Results: In five of the seven participants, we identified CTL epitopes, which contained non-silent mutations in 100% of the sequences obtained from all time points analyzed. Only one participant showed signs of vaccine-induced selection in the rebound plasma virus during the ATI. In this participant, a mutation in one CTL epitope was found in 100% of the plasma RNA sequences, compared to 12% of the proviruses. Notably the rebounding virus formed two distinct clusters in the phylogenetic tree and this participant had the highest rebound doubling time of 2.59 days. Overall, the participants with greater plasma HIV-1 RNA genetic diversity at rebound had a shorter time to viral rebound. Conclusion: We identified CTL epitope changes at baseline, prior to vacc-4x therapy which may affect the potency of this therapeutic vaccine. However, in two participants we identified no mutations of CTL epitopes and they did not show any improved immune responses to vaccination. These findings highlight the challenges of developing immunogenic therapeutic vaccines for HIV Furthermore, we find that the genetic diversity of the virus at rebound relates to the time it takes for virus to rebound. 360LB WITHDRAWN 361 SEX-BASED DIFFERENCES IN TRANSCRIPTOMIC PROFILES AND HIV RESERVOIR CORRELATES Eileen P. Scully 1 , Khader Ghneim 2 , Ashish Sharma 2 , Ainsley Lockhart 3 , Rowena Johnston 4 , Monica Gandhi 5 , Rebecca Hoh 5 , Sharon R. Lewin 6 , Nicolas Chomont 7 , Steven G. Deeks 5 , Rafick-Pierre Sekaly 2 1 Johns Hopkins University, Baltimore, MD, USA, 2 Case Western Reserve University, Cleveland, OH, USA, 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 4 amfAR, New York, NY, USA, 5 University of California San Francisco, San Francisco, CA, USA, 6 University of Melbourne, Melbourne, VIC, Australia, 7 Université de Montréal, Montreal, QC, Canada Background: Biological sex impacts multiple aspects of HIV and the immune response. To identify sex-specific pathways relevant to HIV pathogenesis and cure strategies, we performed transcriptional profiling on a cohort of HIV- positive men and women matched on critical virologic and immunologic factors. Data were analyzed to identify genes and pathways differentially expressed by sex, and gene expression was related to virologic parameters. Methods: Peripheral blood was collected frommen(n=26) and matched reproductive age women(n=26) on fully suppressive ART. RNA was isolated and sequenced with the 3’ digital gene expression platform (Broad Institute). Transcripts were analyzed for differential expression of genes and with gene set enrichment analysis(GSEA) to identify selectively enhanced pathways. Transcriptional profiles were regressed to measures of HIV persistence (total and integrated HIV DNA and unspliced and multiply spliced RNA) for each sex.

Results: 20% of variation in transcriptional profiles is attributable to biological sex (multidimensional scaling analysis). 1429 genes and 16 GSEA pathways were differentially expressed (FDR<0.05). The IFNα(p<0.001, FDR 0.008) and IFNγ(p<0.001, FDR 0.02) pathways were upregulated in women, as seen in HIV uninfected subjects previously. Supervised analysis of interferon pathway genes demonstrated higher expression of antiviral genes (IRF7, ISG15 and MX1) in women. Men and women also showed distinct patterns of inflammasome gene expression with NLRP8, CIITA and NLRC5 upregulated in women; these genes are known to counterbalance pro-inflammatory NLRs. Women and men had distinct transcriptional correlates of HIV reservoir (combined HIV DNA and usRNA). Heme metabolism (anti-inflammatory) and UV response (DNA damage inducer of senescence) pathways positively correlated to the measures of HIV persistence in men. Oxidative response, glycolysis, E2F and Myc pathways (all features of active metabolism and functional T cell responses) were positively correlated with reservoir in women. Conclusion: HIV-infected men and women on fully suppressive ART have distinct transcriptional profiles. Women show enrichment of antiviral pathways along with genes that counterbalance inflammatory components of the inflammasome. Sex-specific analysis of HIV reservoir correlates identifies different gene pathways in men and women. Biological sex determines distinct transcriptional patterns that are related to HIV reservoir, with sex-specific implications for cure strategies 362 THE IMPACT OF ART DURATION ON THE INFECTION OF T CELLS WITHIN ANATOMIC SITES Eunok Lee 1 , Susanne von Stockenstrom 2 , Vincent Morcilla 1 , Wei Shao 3 , Wendy Hartogensis 4 , Peter Bacchetti 4 , Jeffery Milush 4 , Rebecca Hoh 4 , Ma Somsouk 4 , Peter W. Hunt 4 , Rémi Fromentin 5 , Nicolas Chomont 5 , Steven G. Deeks 4 , Frederick M. Hecht 4 , Sarah Palmer 1 1 The Westmead Institute for Medical Research, Westmead, NSW, Australia, 2 Karolinska Institute, Stockholm, Sweden, 3 Frederick National Laboratory for Cancer Research, Frederick, MD, USA, 4 University of California San Francisco, San Francisco, CA, USA, 5 Université de Montréal, Montreal, QC, Canada Background: Understanding the impact of antiretroviral therapy (ART) duration on the dynamics of HIV reservoirs is critical for effective curative strategies. Here, we studied changes in the HIV reservoir size over 3-18 years of ART. We also examined the genetic similarity of HIV sequences found in T cell subsets and plasma viremia. Methods: Using single-genome/proviral sequencing, we performed cross- sectional inter-participant analysis of 1134 HIV p6-RT RNA sequences from pre- and early-ART plasma; and 3963 HIV DNA sequences from naïve, central (CM), transitional (TM), and effector (EM) CD4+ T cells sorted from peripheral blood (PB), lymph node (LN) and gut tissues from 26 participants on effective ART for 3-18 yrs: 12 who initiated ART during acute/early (AHI) and 14 during chronic HIV infection (CHI). HIV infection frequencies in anatomic and cellular sites were computed by maximum likelihood statistics. Expansions of identical sequences (EIS) were determined as ≥2 identical HIV-DNA sequences across all cell types from all anatomic sites in CHI group. Results: In PB, the fold-change in infection frequency per year on ART was similar between AHI and CHI groups across all cell types. For the CHI group, the infection frequency was stable in PB-derived EM cells (fold-change=1.0/yr on ART, 95% CI=0.9-1.2). However, the odds of a viral sequence belonging to EIS increased in PB, most substantially in EM cells (p=0.007). No substantial change of HIV infection frequency was observed in cells from the gut. In LN, the AHI group had a larger decline in infection frequencies compared to the CHI group in each cell type (fold-change=0.092-0.48, p-values=0.0056-0.036). Importantly, for the CHI group, EM cells from the LN contained HIV-DNA sequences that were more often genetically identical to pre- and on-ART plasma HIV-RNA sequences than other LN cell types. Conclusion: The infection frequency of PB-derived EM cells was stable during 3-18 years of ART but the expansions of identical sequences increased which indicates stochastic cellular proliferation and contraction contribute to HIV persistence in these cells. We observed sustained declines in estimated reservoir size in the LN, which changes more substantially among those who started ART during acute infection indicating early ART initiation promotes T cell reconstitution in the LN. However, our data suggest that in LN tissue the replication-competent viral population is more enriched in EM cells.

Poster Abstracts

CROI 2018 126