CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

TNF-alpha, hsCRP). Testing was performed at median of 7.1 yr after ART initiation (time point 1) and again a median of 3.7 yr later (time point 2). Results: Fifty participants (26% female) were evaluated. Intact proviral DNA levels declined significantly between time point 1 (n=50) and time point 2 (n=48): median of 57 and 41 copies/million CD4 cells, respectively; p<0.001 (Figure). By contrast, total proviral DNA was stable: median of 551 and 580 copies/million CD4 cells, respectively. The estimated (median) half-life of decline for intact proviral DNA (n=44 participants) was 6.5 yrs (95% CI 4.5, 11.2), whereas that for total proviral DNA was 22.9 years (95% CI, 11.1 to 60.9). Six participants had decline in intact proviral DNA to undetectable levels. Higher on-ART intact proviral DNA levels correlated with higher on-ART total HIV DNA (r=0.48), higher CA-RNA (r=0.46) and higher SCA (r=0.39) (time point 1; all p-values ≤0.005). No associations were seen between on-ART intact proviral DNA levels and on-ART T cell activation or inflammation. Conclusion: In people on long-term ART, intact proviral DNA levels decline significantly (half-life 6.5 yr), whereas total proviral DNA remains stable over the same time period (half-life 22.9 yr). A subset of individuals had a decline in intact proviral DNA to undetectable levels. The overall decline in intact proviruses implies that cells containing replication-competent proviruses are being lost. Defining the mechanisms involved should inform strategies to accelerate HIV reservoir depletion. The more dynamic nature of the intact proviral landscape, compared with total proviral HIV DNA, supports the use of the IPDA to assess the impact of interventions targeting the HIV reservoir.

withdrawal, viral rebound was delayed in all animals; one remains undetectable at 53 days post-ATI. Conclusion: Previous studies in patients and NHPs demonstrated low-level persistence of virus-specific CAR T cells in vivo, relative to CAR T cells for cancer. To our knowledge, ours is the first study to boost virus-specific CAR T cells in infected, suppressed hosts, and to delay/control post-ATI viral rebound via CAR T cell therapy. Due to the lack of a cytotoxic conditioning regimen, the safety profile of our approach is highly favorable. Our data reinforces the promise of deltaCCR5 CD4CAR T cell therapies for viral reservoir reduction in HIV+ individuals, including a Phase I clinical trial underway at the University of Pennsylvania (NCT03617198).

Oral Abstracts

77 DELAY IN VIRAL REBOUND WITH TLR7 AGONIST, N6-LS, AND PGT121 IN SHIV-INFECTED MACAQUES Denise C. Hsu 1 , Decha Silsorn 2 , Rawiwan Imerbsin 2 , Amarendra Pegu 3 , Dutsadee Inthawong 2 , Jumpol Sopanaporn 2 , Alexandra Schuetz 1 , James Demarest 4 , Merlin L. Robb 5 , John R. Mascola 3 , Romas Geleziunas 6 , Richard A. Koup 3 , Dan Barouch 7 , Nelson L. Michael 5 , Sandhya Vasan 5 1 US Military HIV Research Program in Thailand, Bangkok, Thailand, 2 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 3 NIH, Bethesda, MD, USA, 4 ViiV Healthcare, Research Triangle Park, NC, USA, 5 US Military HIV Research Program, Silver Spring, MD, USA, 6 Gilead Sciences, Inc, Foster City, CA, USA, 7 Beth Israel Deaconess Medical Center, Boston, MA, USA Background: Toll-like receptor (TLR)-7 agonist and PGT121 administration have previously delayed viral rebound and induced SHIV remission after antiretroviral therapy (ART) interruption in macaques that started ART 7 days post SHIV-SF162P3 infection. We evaluated the impact of TLR-7 agonist and dual broadly neutralizing antibodies (bnAb) on viral rebound in SHIV-infected macaques. Methods: Male rhesus macaques (n=16), pre-screened to exclude protective MHC alleles, were inoculated at wk0 with SHIV-1157ipd3N4 intrarectally. ART (tenofovir, emtricitabine and dolutegravir) was initiated on Day14. Active arm (n=8) animals received oral GS-986, every 2 weeks fromwk14-32 and intravenous N6-LS and PGT121 every 2 weeks fromwk24-32 unless anti-drug antibodies (ADA) developed. ART was ceased when plasma levels of N6-LS and PGT121 were <0.25mg/mL. Control animals (n=8) received intravenous saline. Plasma SHIV RNA was assessed by qPCR (limit of detection 10 copies/mL) and soluble markers of immune activation by multiplex assay using Luminex. Results: All animals were SHIV-infected with median SHIV RNA of 5.7 (range 4.1-6.8) log 10 copies/mL on day14. After ART initiation on day14, SHIV RNA became undetectable in all animals by wk8 and remained undetectable until ART interruption. Due to varying ADA, animals received 7-10 doses of GS-986, 2-5 doses of PGT121 and 2-5 doses of N6-LS. At 24hrs post GS-986 dosing, plasma levels of IFNα, IL-1RA, IL-2, IL-6, IL-10, IL-15, MCP-1, MIP-1b, TNF, GM-CSF, IL-13 and MIP-1a increased significantly and viral blips were not detected. In the active arm, %Ki-67+ NK cells also increased at wk24 when compared to wk14 (p=0.031). Total HIV DNA levels in PBMC prior to ART interruption were not significantly different between arms. Median time to viral rebound was 6 weeks in active arm and 3 weeks in control arm (p=0.024, Figure 1). There was no significant difference in post rebound peak or set-point viremia between groups. Conclusion: Administration of GS-986 and dual bNAbs was associated with a modest delay in viral rebound. The effect of timing of ART initiation on seeding of the viral reservoir likely influenced the ability to achieve remission. Evaluating this strategy in humans is warranted.

76 CHIMERIC ANTIGEN RECEPTOR T CELLS CONTROL SHIV REPLICATION IN POST-ATI MACAQUES Blake Rust 1 , Lucrezia Colonna 1 , Katherine Brandenstein 1 , Nikhita H. Poole 1 , Willi Obenza 1 , Colby Maldini 2 , Gavin Ellis 2 , Leslie Kean 3 , James L. Riley 2 , Hans-Peter Kiem 1 , Christopher Peterson 1 1 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 2 University of Pennsylvania, Philadelphia, PA, USA, 3 Boston Children's Hospital, Boston, MA, USA Background: An effective strategy to achieve antiretroviral therapy (ART)-free remission in HIV+ individuals will likely require active and passive approaches. We optimized CD4-based Chimeric Antigen Receptor (CD4CAR) molecules to actively target infected cells, and combined with CCR5 editing to passively protect CD4CAR T cells against infection. This approach was modeled in nonhuman primates (NHPs) infected with simian/human immunodeficiency virus (SHIV) and suppressed long-term on ART. Our goal was to quantify the impact of NHP deltaCCR5 CD4CAR T cells on viral rebound following analytical treatment interruption (ATI). Methods: Rhesus macaques (n = 4) were infected with SHIV, and suppressed by ART for at least 1 year prior to intervention. Autologous T cells were edited with NHP CCR5 CRISPR ribonucleoproteins, then modified with lentiviral vectors expressing HIV/SHIV-specific CD4CAR. CAR T cell products were infused without a conditioning regimen. Transplanted animals received a single dose of cell-associated viral envelope antigen to boost the persistence of these cells in vivo. Flow- and PCR-based assays were used to characterize the T cell infusion product and the persistence of these cells in blood and tissues. Plasma viral load was monitored weekly before and after T cell infusion and ATI. Results: Adjustments to the manufacturing protocol augmented the ratio of CD4 to CD8 CAR T cells, increasing the persistence of CAR+ CD4 lineages in vivo. Infusion of cell-based antigen was well tolerated and led to significant increases in the percentage of CAR+ T cells in peripheral blood. Following ART

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CROI 2020