CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

be resistant to infection with CCR5- and CXCR4-tropic virus. Here, we describe long-term control of plasma viremia in these animals following challenge with the HIV-enveloped simian/human immunodeficiency virus (SHIV) 89.6P. Methods: Two animals were transplanted with autologous HSPCs that were transduced with a clinical grade lentiviral vector (“Cal-1”), which expresses the mC46 fusion inhibitor. Following infusion of gene-modified cells and extensive immune recovery, animals were challenged with SHIV 89.6P by the intravenous route. Flow cytometry and ELISA-based assays were used to monitor changes in relevant immune subsets, namely CD4+ T-cells. Quantitative PCR and sequencing of the 89.6P viral envelope were used to determine viral persistence in peripheral blood and tissues. Results: Peripheral CD4+ T-cell counts have remained within normal range in both animals, over 2 years following infection with SHIV 89.6P. Intriguingly, plasma viral loads have incrementally decreased over the same time frame, with kinetics that are clearly distinct from previously described SHIV controllers. Anti-SHIV antibody and sequencing data suggest that viral replication persists in specific compartments, despite waning plasma viremia. We have applied tandem clonal tracking methodologies to identify persistent infected and protected clones in vivo. Conclusion: Autologous transplantation with mC46-expressing HSPCs results in normalization of T-cell counts, prevents development of AIDS, and drives plasma viremia to nearly undetectable levels; this is especially remarkable in the context of infection with the highly pathogenic SHIV 89.6P. We find clear evidence of SHIV specific responses likely responsible for the long-term viral suppression. We are currently applying strategies that supplement mC46-dependent protection, with the goal of eradicating viral reservoirs and fully eliminating SHIV infection in these otherwise healthy animals. 323 HIV-1 DNA BLOOD RESERVOIRS ARE NOT ALTERED BY HIGH-DOSE CHEMOTHERAPY FOR LYMPHOMA Heloise M Delagreverie 1 , Antoine Chaillon 2 , Laurence Gerard 1 , Marie-Laure Néré 1 , Romain Palich 3 , Sylvain Chawki 1 , Lionel Galicier 1 , Eric Oksenhendler 1 , Marie-Laure Chaix Baudier 1 , Constance Delaugerre 1 1 Saint Louis Hosp, Paris, France, 2 Univ of California San Diego, San Diego, CA, USA, 3 Pitié-Salpêtrière Hosp, Paris, France Background: High-dose chemotherapy (HDC) may have played a major role in the Berlin patient’s cure from HIV by eradicating cellular reservoirs. We describe the impact of high-dose chemotherapy in HIV-related lymphoma patients treated with HDC for autologous stem cell transplantation (ASCT) on HIV-1 reservoir levels and dynamics and on the longitudinal evolution of reservoir diversity. Methods: 6 retrospective HIV-1-related lymphoma patients with sustained viral control, treated with ASCT were included. Blood HIV-1 DNA total burden was measured by quantitative PCR targeting the viral LTR. The C2V3 viral region from 2 pre- and 2 post-ASCT longitudinal blood samples per patient (time frame 5-24 months) was amplified by nested PCR before deep-sequencing analysis. After quality filtering, haplotype reconstruction allowed the evaluation of molecular diversity (TN93) and compartmentalization between timepoints (Fst and Slatkin Maddison approaches) and the inferring of maximum likelihood (ML) phylogeny. T cell subsets were quantified by flow cytometry according to CD45RA and CCR7 expression. Results: Mean HIV DNA quantification in PBMC over 2 years of follow-up was stable with no difference between pre- and post-ASCT periods (2.91 vs 2.65 log10 copies/10^6 cells, NS) and was measurable as early as 8 days post-ASCT. Deep sequencing of C2V3 cell-associated DNA yielded a median (IQR) depth of 4,955 (3,976-7,587) reads, further collapsed into 23 (10-31) haplotypes per sample. In 5 out of 6 (83%) participants, haplotype pools were not altered after ASCT and there was no evidence of compartmentalization of viral populations over time. Longitudinal viral diversity dropped transiently after high-dose chemotherapy/ASCT but rose back to pre-ASCT numbers (1.5-6%mean pairwise diversity estimates). Blood HIV reservoirs were thus restored to the original frequency of infected PBMC and viral haplotype variety. In addition, the median (range) fraction of memory T cells among CD4+ cells in the first 3 months post ASCT was 96.90% (89.33-98.73), suggesting early replenishment of the blood CD4+ pool frommature memory T cells after ASCT. Conclusion: Deep sequencing of HIV-1 reservoir after ASCT for HIV-related lymphoma reveals fast viral reservoir reconstitution frommemory CD4+ cells. These results point to the utmost importance of the management of infected mature memory T cells present in HIV+ autologous transplants, in the setting of present gene therapy trials in HIV-related lymphoma patients treated with ASCT. 324 THE IMPACT OF IMMUNOGLOBULIN IN PRIMARY HIV INFECTION ON THE HIV RESERVOIR Juan Tiraboschi 1 , Prabhjeet Phalora 2 , Nicola Robinson 2 , Emily Hopkins 2 , Steve Kaye 3 , Jeremy Sanderson 1 , Sarah Fidler 3 , Paul Klenerman 2 , John Frater 2 , Julie Fox 4 1 Guy´s and St Thomas´ NHS Fndn Trust, London, UK, 2 Univ of Oxford, Oxford, UK, 3 Imperial Coll London, London, UK, 4 King’s Coll London, London, UK Background: Antiretroviral therapy (ART) during primary HIV infection (PHI) restricts the HIV reservoir, but additional interventions will be necessary to induce a cure. Candidates include the passive infusion of neutralising antibodies. Intravenous immunoglobulin (IVIG) is not HIV-specific but is safe and has been reported to temporarily reduce the HIV reservoir in chronic HIV infection. We present a randomised controlled trial (RCT) to determine whether IVIG in PHI has a greater impact on the reservoir than reported for chronic infection. The aimwas to investigate whether IVIG plus ART in PHI reduces the HIV reservoir and immune activation compared with ART alone. Methods: Ten males with PHI (Fiebig II-IV) initiated ART (TNF/FTC/DRVr/RAL) at diagnosis and were randomised to ART alone or ART plus 5 days IVIG once virally suppressed (w19). Blood samples were evaluated for viral reservoir (total DNA, low copy VL, RNA transcripts), immune activation (HLA DR, CD38), immune exhaustion (PD-1, Tim-3. Lag-3) and microbial translocation (16s RNA). Flexible sigmoidoscopy was performed (n =10) at weeks 19, 24 and 48, and gut proviral DNA and cell numbers determined. Results: From baseline to week 48, there was no difference in the decline in total DNA in the 2 groups (controls:-5045.9: cases -7513.1; p=0.49) or in plasma low copy RNA (p=0.77). However, there was a significant decrease in mean total blood HIV DNA fromweek 19 to 24 in the ART alone group (p=0.04) but no significant change in those receiving IVIG (-2583.7 vs 207.7 copies/million CD4 cells, respectively). In the gut, total HIV DNA declined fromw19 to w48, with no significant differences between arms (10891- vs 8965 copies/million CD4 cells, respectively; p =0.67). No viral blips occurred during IVIG. Plasma levels of CRP, levels of immune activation (frequencies of CD4 and CD8 T cells expressing CD38 and HLA-DR), immune exhaustion (CD8 Tim3, Lag3, Pd-1), microbial translocation (16sRNA), and CD4:CD8 ratio were similar between arms for all comparisons. Conclusion: Although safe, IVIG in PHI did not impact the viral reservoir, immune function or microbial translocation in peripheral blood or gut tissue at week 48. The transient halt in decline in blood HIV DNA between weeks 19 to 24 in those receiving IVIG is intriguing. The rapid recruitment and uptake of optional gut biopsies in all highlights the willingness of individuals with PHI to take part in HIV cure research. 325 RATES OF VIRAL DECAY IN HIV-1 CONTROLLERS INITIATING ANTIRETROVIRAL THERAPY Jonathan Li 1 , Heloise M. Delagreverie 2 , Rachel Getz 1 , Christina Lalama 3 , Ronald Bosch 3 , Daniel R. Kuritzkes 1 , Alan Landay 4 , Florencia Pereyra 1 , Paul E. Sax 1 , for the AIDS ClinicalTrials Group A5308 StudyTeam 1 Brigham and Women’s Hosp, Harvard Med Sch, Boston, MA, USA, 2 Saint Louis Hosp, Paris, France, 3 Harvard Univ, Boston, MA, USA, 4 Rush Univ Med Cntr, Chicago, IL, USA Background: Despite viremic control, many HIV controllers (HCs) have detectable viral replication and elevated systemic inflammation. Initiation of ART in HCs further decreases viral load, but the rate of viral decay has not been compared to non-controllers (NCs). Viral decay rates may provide additional insights on the composition and half-life of HIV- infected cellular reservoirs. Methods: ACTG A5308 is a prospective, single-arm, open-label study of fixed dose RPV/FTC/TDF in treatment-naive HCs with viral loads (VLs) <500 cp/mL for ≥12 months. Plasma VLs were measured by the integrase single-copy assay (iSCA) at study entry and 0, 2, 7, 10, 14, 21, 28, 56 and 84 days after ART initiation. Soluble inflammatory markers (IL-6, IP-10, hs-CRP, sCD14, sCD163, D-Dimer) were measured by ELISA at entry and 0, 4 and 12 weeks after ART initiation. Participant-specific phase 1 viral decay rates were estimated with a censored-data linear mixed-effects model using iSCA data from day 0 to 11 of ART in those with entry iSCA ≥0.4 cp/mL. Phase 2 decay rates were estimated from day 8 to 59 of ART in those with sufficient iSCA ≥0.4 cp/mL. Exact Wilcoxon rank-sum test was performed to compare decay parameters for HCs with 41 NCs who initiated NNRTI-based regimens in previous studies.

Poster and Themed Discussion Abstracts

CROI 2017 127