CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

1 Institute of Tropical Medicine, Antwerp, Belgium, 2 HIV Cure Research Center, Ghent University, Ghent, Belgium, 3 Saint-Pierre University Hospital, Brussels, Belgium, 4 Vrije Universiteit Brussel, Brussels, Belgium, 5 Ghent University, Ghent, Belgium, 6 Antwerp University Hospital, Antwerp, Belgium Background: No single parameter reliably predicts post-treatment control (PTC) among HIV infected patients. However, both total HIV-1 DNA (tDNA) and cell-associated RNA (caRNA) have been individually associated to delayed viral rebound after ATI. We evaluated the predictive value of the combination of low DNA and caRNA in the identification of PTC. Methods: The study is a two-step single armmulti-centric non-randomized prospective trial (NCT02590354). Major inclusion criteria in step 1 were: nadir CD4+ T-cell count >350cells/µl and plasma viral load (pVL) <50 cps/ml since ≥2 years. The size of the HIV reservoir was determined by droplet digital PCR measurement of tDNA and caRNA in peripheral blood mononuclear cells (PBMCs). In step 2, consenting participants with tDNA <66 cps/10 6 PBMCs and caRNA <10 cps/10 6 PBMCs underwent a leucapheresis prior ATI. cART was re-initiated whenever pVL, measured every other week, was >1,000 cps/ml at two consecutive measurements or at pVL > 10,000 cps/ml. tDNA and caRNA were measured at every visit during ATI as well as 4 and 12 weeks after cART re-initiation. Quantitative viral outgrowth assays (qVOA), viral release assays (VRA) and ultra-sensitive pVL were performed on pre-ATI samples. Associations between clinical, virological or immunological parameters and viral rebound dynamics were assessed with Kaplan-Meier estimates and Cox proportional hazard models. Results: Of the 114 participants, 37 (32.5%) met the viral reservoir criteria for ATI. Of them, 16 (14.0%) consented and underwent ATI. All 16 participants experienced rapid viral rebound two to eight weeks after ATI (figure), with 13/16 (81.3%) reporting an adverse event (AE) but none with serious AE. All participants suppressed viremia to levels below the limit of detection within 14 weeks of cART re-initiation. tDNA and caRNA returned to baseline levels within the 12 weeks after cART re-initiation. No correlations were observed between viral rebound dynamics and current or nadir CD4+ T-cell count, ultra-sensitive pVL, tDNA or caRNA, qVOA, VRA or any other clinical parameters. Conclusion: We report on the first prospective study evaluating ATI in participants selected on the basis of a very small and transcriptionally silent HIV reservoir. No PTC was identified. ATI was shown to be safe, despite rapid viral rebound. The impact of ATI on the reservoir size after cART re-initiation was limited. None of the measured baseline parameters were predictive for viral rebound dynamics.

1 Emory Vaccine Center, Atlanta, GA, USA, 2 Oregon Health and Sciences University, Portland, OR, USA, 3 Leidos Biomedical Research, Inc, Frederick, MD, USA, 4 NantKworks, Culver City, CA, USA, 5 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background: The current paradigm in HIV cure research is that virus production must be reactivated in latently infected cells prior to clearance (shock and kill). Since depletion of CD8+ lymphocytes in SIV-infected ART- treated rhesus macaques (RM) results in increased plasma viremia, we propose that CD8 depletion may act synergistically with latency reversing agents (LRA) in reactivating virus production. To test this hypothesis we used the IL-15 superagonist N-803, an agent that shows LRA activity in vitro and may also boost antiviral cellular immune responses. Methods: 35 SIV-infected RM started ART 8 weeks post-infection. After 1 year, 7 RM received four weekly doses of N-803 (100 µg/kg), 14 received 50 mg/kg of the CD8α-depleting Ab MT-807R1, and 14 RM received both treatments. All animals underwent ART interruption 3 weeks after the last N-803 dose and/ or CD8 reconstitution. SIV reactivation was monitored by plasma viremia and RNAscope analysis in lymph node samples. The size of the viral reservoir was assessed by total cell-associated SIV DNA. Immunological changes were studied by flow cytometry and RNA sequencing. Diversity of the virus emerging after N-803 and/or CD8 depletion was assessed via single genome amplification. Results: In ART-treated RM, N-803 alone did not reactivate virus production; however, its administration in CD8-depleted RM resulted in loss of virus suppression (>60 copies/ml) in 14/14 animals (100%) in 41/56 samples (73.2%) collected 1 week after each dose. In addition, viremia >1,000 copies/ ml was observed in 6/14 animals (42.9%) and 13/56 (23.2%) time points, with a maximum of 21,000 SIVgag copies/mL. Preliminary virus sequence analysis indicated a diverse range of circulating virus after CD8 depletion and N-803 treatment. Despite this very robust level of virus reactivation, all groups of RM showed stable levels of cell-associated SIV DNA in CD4+ T cells following treatment and a rapid rebound of viremia after ART interruption. Conclusion: N-803 administration in CD8-depleted, ART-treated SIV-infected RM induces the most robust and persistent reversal of latency observed to date in humans or nonhuman primates. In absence of a clearance intervention, we did not observe a significant reduction of the reservoir size. Combining N-803 and CD8 depletion with an immune-clearing component (i.e. neutralizing antibodies, CD4 mimetics or immunotoxins) may be a powerful shock and kill strategy that profoundly affects reservoir size and stability in ART-treated HIV/ SIV infections.

Poster Abstracts

390 N-803 INDUCES ROBUST SIV REACTIVATION IN ART-TREATED CD8- DEPLETED MACAQUES Julia B. McBrien 1 , Maud Mavigner 1 , Stacey A. Smith 1 , Erick R. White 1 , Thomas Vanderford 1 , Jake D. Estes 2 , Jeffrey D. Lifson 3 , John H. Lee 4 , Jeffrey T. Safrit 4 , J. V. Garcia 5 , Mirko Paiardini 1 , Steven E. Bosinger 1 , Cynthia Derdeyn 1 , Ann Chahroudi 1 , Guido Silvestri 1

CROI 2019 140