CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

344 BRENTUXIMAB VEDOTIN REDUCES CD30 EXPRESSION AND GUT HIV DNA LEVELS IN HUMANIZED MICE Cecilia Prator 1 , Louise Hogan 1 , Shreya Kumar 1 , Cassandra Thanh 1 , Serah Tanno 2 , Tony Pan 1 , Erica Gibson 1 , Norman G. Jones 1 , Jeffrey M. Milush 1 , Vladimir Vrbanac 2 , Timothy J. Henrich 1 1 University of California San Francisco, San Francisco, CA, USA, 2 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA Background: CD30 is preferentially expressed in HIV-infected and viral transcriptionally active CD4 T cells from viremic and ART suppressed individuals. We observed treatment with anti-CD30 antibody drug conjugate, brentuximab vedotin (BV), leads to reduced cell-associated HIV DNA in vitro and transient decreases in cell-associated HIV RNA in vivo. The impact of anti-CD30 therapy on tissue measures of HIV burden is unknown. Methods: Humanized BLT mice were initiated on daily TDF, FTC, and DTG by oral gavage approximately 3 weeks following intraperitoneal infection with HIV-1 JR-CSF. After mice achieved viral suppression they were divided into three treatment cohorts: [1] ART alone control (N=16); [2] ART and 3 intraperitoneal (IP) weekly infusions of 20 mg/kg BV (N=18); [3] ART, BV and a single 2.5/10 μg IP injection of IL15/IL15RaFC given with the first dose of BV (N=18). Three weeks after the last BV infusion, mice were sacrificed and HIV DNA and RNA were isolated from blood, ileocecal junction, spleen, lymph nodes, and liver. Results: Although the frequency of CD30 expression on human CD4 T cells was low in all cohorts, BV with and without IL15/IL15RaFC led to significant reduction in the frequency of human CD45+CD4+ T cells expressing CD30 (0.09% in ART controls, 0.05% in both treatment cohorts; P=0.03) and HLA-DR (4.0%, 0.6%, 0.6%, respectively; all P<0.01). BV with and without IL15/IL15RaFC also led to the reduced frequency of effector memory CD4 T cells (14% to 8% and 6%, respectively) and increased frequency of naive CD4+ T cells in peripheral blood (68% to 71% and 75%, respectively). Overall, there were no significant changes in blood, spleen, lymph node, and liver levels of cell-associated HIV RNA or DNA, but BV treated mice had significantly lower HIV DNA measured in gut tissue compared with ART-only controls at the time of necropsy (HIV DNA 164 c/10 6 vs 21,788 c/10 6 cells; P=0.04). Gut HIV DNA levels were similar to controls in mice that received concomitant BV and IL15/IL15RaFC. Conclusion: BV treatment in BLT mice decreased the frequency of CD4 T cells expressing CD30, markers of T cell activation, and effector memory phenotype. BV alone, but not in combination with IL15/IL15RaFC, led to decreased gut HIV DNA levels. However, the high percentage of circulating naive lymphocytes and overall low CD30 expression in the BLT mouse model may have dampened the impact of anti-CD30 therapy on measures of HIV persistence.

antibody GS-9721 and VES (N=9), or sham control (N=7) every 2 weeks. At week 42 following initial antibody dosing, which was 24 weeks after the final antibody and VES doses, ART was discontinued and viral rebound was monitored for 140 days. Results: PGT121 and GS-9721 infusion resulted in 24 weeks of therapeutic antibody levels without the development of ADA, 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 and increased levels of serum cytokines. Following ART discontinuation, 100% (7 of 7) of sham controls exhibited rapid viral rebound with a median rebound time of 21 [IQR 14-21] days. In contrast, only 50% (4 of 8) of PGT121 + VES treated animals and 66% (6 of 9) of GS-9721 + VES treated animals rebounded by day 140 after ART discontinuation (P=0.05, Fisher’s exact test compared with sham controls) and showed a delay in the median rebound time of 28 [IQR 21-140+] days. Conclusion: In SHIV-infected rhesus monkeys that initiated ART after 1 year of chronic infection and that were virologically suppressed with ART for 2.5 years, administration of PGT121 or GS-9721 with VES prevented viral rebound in 41% (7 of 17) of animals following ART discontinuation. These data suggest therapeutic efficacy of broadly neutralizing antibodies with TLR7 stimulation in targeting the viral reservoir in the rarely used but clinically more relevant model of chronic SHIV infection in rhesus monkeys. 346LB SUSTAINED HIV REMISSION IN THE LONDON PATIENT: THE CASE FOR HIV CURE Ravindra K. Gupta 1 , Dimitra Peppa 2 , Matthew Pace 2 , John P. Thornhill 3 , Eleni Nastouli 4 , Paul Grant 4 , Laura McCoy 4 , Andrew Innes 3 , Simon Edwards 4 , Annemarie Wensing 5 , Monique Nijhuis 5 , Javier Martinez-Picado 6 , John Frater 2 , Eduardo Olavarria 7 , for the CHERUB and IciStem Study Groups 1 Cambridge University, Cambridge, UK, 2 University of Oxford, Oxford, UK, 3 Imperial College Healthcare NHS Trust, London, UK, 4 University College London, London, UK, 5 University Medical Center Utrecht, Utrecht, Netherlands, 6 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 7 Imperial College London, London, UK Background: The London Patient underwent allogeneic stem cell transplantation with d32 homozygous tissue and remission was reported at 18 months. Here we present longer term data including tissue sampling. Methods: Ultra sensitive plasma, semen and CSF viral load assays were used to detect HIV-1 RNA. The method for HIV DNA quantification in gut biopsies and lymph nodes was as follows: tissue samples from each site were mixed with ceramic beads and Qiagen RLT Plus buffer. The tube contents were then homogenised using a MagNA Lyser (Roche) set at 6000rpm for 45 seconds. Genomic DNA was then extracted using a Qiagen AllPrep DNA/RNA Mini Kit. Cell-copy number and total HIV DNA levels were quantified both in triplicate using droplet digital PCR. Results: HIV-1 viral load in plasma and proviral HIV DNA in CD4 cells have remained below detection up to 30 months. The most recent CD4 count was 370 cells/Ul (20.3%) and CD4/CD8 ratio 0.65. Plasma HIV antibodies have remained undetectable by western blot except low level Env reactivity. Semen viral load was below limit of detection in both plasma (LLD in seminal plasma is <12 copies/ml) and cells (LLD 10 copies/million cells).CSF protein and glucose were normal with no cells detected. HIV-1 viral load in CSF was below detection limit (LLD 1 copy/ml). HIV DNA by ddPCR was negative in Rectum, Caecum, sigmoid and T.Ileum. Lymph node tissue from the axilla was positive for LTR and Env at around 30 copies/million cells, but negative for packaging signal and integrase. The intact proviral DNA assay (IPDA) was negative. Conclusion: The London patient has been in HIV remission for 2.5 years with no detectable replication competent virus in blood, CSF, intestinal tissue or lymphoid tissue. Donor chimerism has been maintained at 99% in T cells. We conclude that this represents HIV-1 cure with evidence of low level defective HIV genomes in lymphoid tissue.

Poster Abstracts

345LB PGT121 AND VESATOLIMOD IN CHRONICALLY TREATED SHIV-INFECTED RHESUS MONKEYS Dan Barouch 1 , Noe Mercado 1 , Abishek Chandrashekar 1 , Erica Borducchi 1 , Joseph Nkolola 1 , Brian A. Carr 2 , Nathan D. Thomsen 2 , Romas Geleziunas 2 1 Beth Israel Deaconess Medical Center, Boston, MA, USA, 2 Gilead Sciences, Inc, Foster City, CA, USA Background: We have previously reported that administration of the broadly neutralizing antibody PGT121 with the TLR7 agonist vesatolimod (VES) delayed or prevented viral rebound in SHIV-infected rhesus monkeys following ART discontinuation in animals that initiated ART early during acute infection. However, the efficacy of bNAbs has not previously been evaluated in the more clinically relevant model of animals that initiated ART during chronic infection with extended ART suppression. Methods: 24 rhesus monkeys were infected with SHIV-SF162P3 and initiated daily ART (TDF/FTC/DTG) after 12 months of chronic infection. Following 30 months of continuous daily suppressive ART, animals received 10 infusions of 10 mg/kg PGT121 and 0.15 mg/kg VES (N=8), an Fc-modified version of this

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