CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

Methods: We conducted 2 studies in SHIV-infected ART-suppressed rhesus macaques (RM) to evaluate the IL-15 superagonist, N-803 to enhance virus- specific effector cells, in conjunction with broadly neutralizing antibodies (bNAbs, 10-1074 and 3BNC117). Thirty-six RMs were rectally infected with SHIV- AD8. RMs received ART at ~50 days post infection (Study 1, n=20 and Study 2, n=16) and virologic suppression was maintained for 65 or 60 weeks PI for each study, respectively. In Study 1, ART-suppressed monkeys received 6 doses of N-803 alone (n=5), 2 doses of 10-1074 alone (n=5), a combination of N-803 and 10-1074 (n=5), or vehicle control (n=5). In Study 2, ART-suppressed RMs received 6 doses of N-803 and 3 doses of both 10-1074 and 3BNC117 (n=8) or the vehicle control (n=8). Plasma SHIV RNA levels were measured and viral DNA were quantified in PBMC, colon and lymph node (LN) biopsies taken pre- and post- treatment. Modulation of immune populations, including T, B and NK cells, were monitored longitudinally. After monitored washout of bNAbs in plasma, ART was discontinued. Results: In both studies, blood NK cells showed peak activation at 48hrs post N-803 administration throughout the dosing period. Memory T cells were preferentially activated by N-803, and CD8+ T cells demonstrated more robust expansion during the dosing period. No immune activation of PBMC was associated with bNAb treatment. We observed no change in integrated SHIV DNA between pre- and post- treatment timepoints in either PBMC or LN tissues (Study 1). In Study 1, plasma viral rebound kinetics in RMs treated with either N-803 or 10-1074 alone, or in combination, were comparable to the control group after ART discontinuation. However, 3 of 5 combination treated RMs showed durable control of viremia after initial low-level rebound. In Study 2, 6 of 8 combination-treated (N-803/bNAbs) RMs exhibited durable control of viremia beyond week 25 following initial low-level rebound. Conclusion: Repeated co-dosing of N-803 and bNAbs is safe and may facilitate long-term viral control and remission in the absence of ART. 80 A MENDELIAN RANDOMIZATION ANALYSIS OF PROTEIN BIOMARKERS AND CVD IN PERSONS WITH HIV Cavan Reilly 1 , James Pankow 1 , Jason V. Baker 2 , Álvaro H. Borges 3 , Mark Polizzotto 4 , Shweta Sharma 1 , Sandra Safo 1 , for the INSIGHT Study Group 1 University of Minnesota, Minneapolis, MN, USA, 2 Hennepin County Medical Center, Minneapolis, MN, USA, 3 Rigshospitalet, Copenhagen, Denmark, 4 Kirby Institute, Sydney, NSW, Australia Background: Treated HIV+ persons have excess risk for CVD yet the mechanisms explaining this remain poorly understood. Here we used a Mendelian randomization (MR) approach to assess causality of circulating proteins on CVD risk among participants in INSIGHT trials. Methods: We identified participants in 4 clinical trials conducted by INSIGHT (FIRST, ESPRIT, SMART and START) who experienced a clinical event (composite outcome of AIDS, serious non-AIDS including CVD, and death) and individually matched them (1:2) with study-specific controls who did not. Baseline plasma samples were used to measure protein levels using 5 panels made by OLINK (panels: CVD2, CVD3, immune response, cardiometabolic and inflammation). Genome-wide genotypic data was available for all. Proteins that passed quality control were screened for an association with the CVD outcome (MI, coronary revascularization, stroke, CVD death) while controlling for matching, demographics, hypertension, diabetes and study specific treatment group effects using a 5% significance level. Proteins associated with CVD outcomes were then tested for an association with genetic variants within 5Kb of the corresponding protein-coding gene while controlling for matching, demographics and study. Significant SNPs (family-wise p<5% for each protein) were used to construct haplotypes. The number of copies of the most common haplotype was used as an instrumental variable in a linear MR analysis (with a 5% level test). If only a single significant SNP was detected, that SNP was used as an instrument. It can be demonstrated that this protein screening approach controls the family-wise error rate at 5% across all MR tests. Results: This analysis included 1493 participants (500 cases; 131 with CVD) with mean follow-up of 6 years. Of the 459 distinct proteins represented at least once on the panels, 389 passed quality control measures. Of these proteins, 89 were associated with CVD. Of these 89, 38 were associated with at least 1 SNP in the corresponding gene. MR analysis detected IL6RA, AXL, CHI3L1, SCGB3A2, GAS6 and IL1RL2 as potential causal factors that impact CVD outcomes (replicating a previous finding for IL6RA among HIV- people). Table 1 summarizes these associations of proteins/SNPs with CVD risk.

78LB COMBINED ACTIVE AND PASSIVE IMMUNIZATION IN SHIV-INFECTED RHESUS MONKEYS Dan Barouch 1 , Noe Mercado 1 , Abishek Chandrashekar 1 , Erica Borducchi 1 , Joseph Nkolola 1 , Maria Pau 2 , Hanneke Schuitemaker 2 , Merlin L. Robb 3 , Nelson L. Michael 4 , Romas Geleziunas 5 1 Beth Israel Deaconess Medical Center, Boston, MA, USA, 2 Janssen Prevention and Vaccines, Leiden, Netherlands, 3 Henry M Jackson Foundation, Rockville, MD, USA, 4 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 5 Gilead Sciences, Inc, Foster City, CA, USA Background: Our group and others have previously reported that therapeutic immunization can result in post-rebound virologic control in SHIV-infected rhesus monkeys following ART discontinuation, and that administration of broadly neutralizing antibodies (bNAbs) can delay or prevent viral rebound. The potential of combined active and passive immunization as an HIV-1 cure strategy has not previously been evaluated. Methods: 49 rhesus monkeys were infected with SHIV-SF162P3 and initiated ART (TDF/FTC/DTG) on day 9 of infection. Following 24 weeks of continuous daily suppressive ART, animals received 4 immunizations with Ad26/MVA vaccines at weeks 24/36/48/60 (N=12), 5 infusions of 10 mg/kg PGT121 every 2 weeks fromweeks 64-72 (N=12), both Ad26/MVA vaccines and PGT121 (N=10), or sham controls (N=15). All groups except the sham controls received 10 doses of 0.15 mg/kg of the TLR7 agonist vesatolimod (VES) by oral gavage (every 2 weeks fromweeks 50-72). At week 86, ART was discontinued and viral rebound was monitored for 140 days. Results: Ad26/MVA vaccination resulted in increased magnitude and breadth of SHIV-specific cellular and humoral immune responses. PGT121 infusion resulted in 14 weeks of therapeutic antibody levels followed by a decline to undetectable levels prior to ART discontinuation. VES administration led to activation of multiple cellular immune subsets including CD4+ T lymphocytes. Following ART discontinuation, 100% (15 of 15) of sham controls exhibited rapid viral rebound, and all animals in this group remained viremic by day 140 following ART discontinuation. 100% (12 of 12) of the Ad26/MVA + VES vaccinated animals also rebounded, but 3 animals demonstrated post-rebound virologic control to undetectable levels. In contrast, only 66% (8 of 12) of PGT121 + VES treated animals and 60% (6 of 10) of Ad26/MVA + PGT121 + VES treated animals rebounded (P=0.016, Fisher’s exact test compared with sham controls). Moreover, only 40% (4 of 10) of Ad26/MVA + PGT121 + VES treated animals were viremic by day 140 following ART discontinuation (P=0.001, Fisher’s exact test compared with sham controls). Conclusion: Combined active and passive immunization with TLR7 stimulation resulted in both delayed viral rebound and post-rebound virologic control following ART discontinuation in SHIV-infected rhesus monkeys that initiated ART during acute infection. This multi-pronged approach represents a novel HIV-1 cure strategy. So-Yon Lim 1 , Christa E. Osuna 1 , Jina Lee 1 , Daniela Silva-Ayala 1 , Pratik Vikhe 1 , Elsa Chen 1 , Stephanie Lundgren 1 , Margaret Eliot 1 , Dane Schalk 2 , Nancy Schultz- Darken 2 , Michael S. Seaman 1 , Jeffrey T. Safrit 3 , R. Brad Jones 4 , Douglas Nixon 4 , James Whitney 1 1 Beth Israel Deaconess Medical Center, Boston, MA, USA, 2 Wisconsin National Primate Research Center, Madison, WI, USA, 3 NantKworks, Culver City, CA, USA, 4 Weill Cornell Medicine, New York, NY, USA Background: Latent reservoirs of replication-competent HIV-1 persist in patients on antiretroviral therapy (ART) and represent the major obstacle to HIV eradication efforts. Considerable effort has been directed to develop and evaluate novel remission strategies to enhance virus-specific immune responses in ART-suppressed patients. 79LB COMBINATION IL-15 THERAPY IN A SHIV NHP MODEL

Oral Abstracts

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CROI 2020