CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: This data suggest that CCR5 Δ 32/ Δ 32 CB HCT can successfully eliminate HIV-1 and render the recipient’s T cells resistant to HIV-1 infection. This strongly support the use of CB as a platform for a broader application to other HIV-1 infected individuals with severe hematological malignances. 433 CCR5 Editing in Hematopoietic Stem Cells in a Nonhuman Primate Model of HIV/AIDS

Christopher W. Peterson 1 ; JianbinWang 2 ; Patricia Polacino 3 ; Michael C. Holmes 2 ; Shiu-Lok Hu 3 ; Philip D. Gregory 2 ; Hans-Peter Kiem 1 1 Fred Hutchinson Cancer Research Center, Seattle, WA, US; 2 Sangamo BioSciences, Inc., Richmond, CA, US; 3 University of Washington, Seattle, WA, US

Background: Hematopoietic stem cell (HSC) transplantation remains the only clinically observed path to functional cure of HIV infection. To better understand the mechanism of HSC-driven HIV control, and apply this therapy to a greater number of patients, we have developed a model of combination antiretroviral therapy (cART)-suppressed HIV infection in the pigtailed macaque, applicable to both gene therapy- and allogeneic transplant-based cure strategies. Following transplantation of HIV-resistant, autologous cells into conditioned animals, we are evaluating the extent to which protected cell progeny impede infection by SIV/HIV (SHIV) chimeric virus in vivo . Methods: Animals are challenged with SHIV virus containing an HIV envelope, after which a 3-drug cART regimen is initiated. Autologous HSCs are engineered to resist infection through targeted disruption of the CCR5 genetic locus using Zinc Finger Nucleases (ZFNs). Engraftment, persistence, and SHIV response of these autologous stem cells and their progeny are measured in vivo . Results: SHIV infection results in sustained viremia with consequent reductions in CD4 + T cells in peripheral blood and secondary lymphoid tissues. Moreover, administration of three-drug cART leads to rapid and durable suppression of plasma viremia to <30 copies/mL plasma - suggesting that this model recapitulates key features of HIV infection and treatment in humans. CCR5 targeting experiments yield up to 60% gene disruption in CD34 + cells ex vivo , translating to approximately 5% disruption in vivo following transplant. Importantly, up to 10% of transplanted cells carry two disrupted alleles of CCR5; these cells should preferentially reconstitute CD4 + T-cell pools and other susceptible subsets following SHIV challenge. Consistent with this prediction, our preliminary data suggest that CCR5-deleted cells undergo positive selection following SHIV challenge in vivo . Conclusions: Our pigtailed macaque model of HIV infection and cART represents a promising platform for modeling functional cure strategies. Here we show that CCR5 deletion does not impair HSC engraftment or differentiation, and that CCR5-deleted cells may undergo SHIV-dependent positive selection even when present at low levels. Our model enables the evaluation of novel therapeutic approaches in the clinically relevant context of cART controlled SHIV infection - a setting of particular importance to approaches aimed at addressing the viral reservoir. 434 Cytoxan Enhancement of SB-728-T Engraftment: A Strategy to Improve Anti-HIV Response Gary Blick 2 ; Jay Lalezari 3 ; Ricky Hsu 4 ; Erin DeJesus 5 ;Trevor Hawkins 6 ; RonaldT. Mitsuyasu 7 ; ShelleyWang 1 ; Gary Lee 1 ; Winson Tang 1 ; Dale Ando 1 1 Sangamo BioSciences, Inc., Richmond, CA, US; 2 CIRCLE CARE Center, Norwalk, CT, US; 3 Quest Clinical Research, San Francisco, CA, US; 4 New York University School of Medicine, New York, NY, US; 5 Orlando Immunology Center, Orlando, FL, US; 6 Southwest Care Center, Santa Fe, NM, US; 7 University of California Los Angeles CARE Center, Los Angeles, CA, US Background: Administration of CCR5 modified autologous CD4 cells (SB-728-T) is safe and well-tolerated and results in increases in total CD4 counts. The modified cells traffic to lymphoid tissues and have a selective survival advantage during ART treatment interruption (TI). Studies in CCR5 Δ 32 heterozygote HIV subjects showed VL reductions during TI correlated with levels of engraftment of circulating bi-allelic CCR5-modified cells supporting the importance of maximizing engraftment of modified cells. We have previously presented preliminary data on the use of low dose cyclophosphamide (CTX) to enhance this process. We now report the final results of this dose ranging study. Methods: A dose escalation study of IV CTX, with doses ranging from 100 mg/m 2 to 2 g/m 2 (n=3-6/cohort), administered 1-3 days prior to SB-728-T (>90% CD4, <1% CD8) infusion was performed in 18 aviremic, ART-treated HIV subjects with CD4 T cells > 500/uL. Results: CTX was well tolerated with low grade GI side-effects at doses up to 1 g/m 2 . Grade 3 and 4 neutropenia requiring G-CSF developed at 1.5 and 2.0 g/m 2 CTX. A dose-related increase in CD4 count and engraftment of bi-allelic CCR5 modified cells was observed with CTX doses up to 1 g/m 2 but did not increase at 2.0 and 1.5 g/m 2 . By comparison, there was a progressive decline in CD8 cells with CTX dose escalation. Data in the table is expressed as Mean + SE; changes as Day 7 relative to pre-treatment baseline. A 1-log VL reduction from peak was seen in 1 subject each at 100 and 500 mg/m 2 of CTX while 1 subject each at the 1 and 1.5 g/m 2 dose level had a 2-log decline during TI. At the conclusion of the study, 3 additional subjects were conditioned with 1 g/m 2 of CTX and administered CCR5 modified T cells containing 40.5+5.6% CD4 and 46.9+6.4% CD8 T cells. CD8 count increased by a mean of 2590/uL at 7 days in the 2 subjects with data available for analysis. The VL in the first subject remains undetectable 5 weeks after TI initiation versus a median duration of 15+3 days in subjects who received only SB-728T.

Poster Abstracts

Conclusions: CTX conditioning is well tolerated and was associated with increased engraftment of CCR5-modified T cells at doses up to 1 g/m 2 in HIV subjects. CTX conditioning may be a useful strategy to maximize the engraftment and anti-viral effects of SB-728-T. The effects of co-administering CD8 cells with SB-728-T on VL will be presented.

TUESDAY, FEBRUARY 24, 2015 Session P-G1 Poster Session

Poster Hall

2:30 pm– 4:00 pm CNS Reservoirs 435 Highly Precise Measurements of HIV DNA in CSF and Blood by Droplet Digital PCR Michelli Faria de Oliveira 1 ; Sara Gianella 1 ; Scott Letendre 2 ; Konrad Scheffler 1 ; Sergei L. Kosakovsky Pond 1 ; Davey M. Smith 1 ; Matt Strain 1 ; Ronald J. Ellis 2 1 University of California San Diego, La Jolla, CA, US; 2 HIV Neurobehavioral Research Center, San Diego, CA, US

Background: We investigated associations between HIV DNA reservoir dynamics in cerebrospinal fluid (CSF) and blood in subjects with or without antiretroviral therapy (ART), to better understand the dynamics of these critical targets for eradication, and to gauge how well the HIV DNA reservoir in anatomic compartments can be predicted by measurements in peripheral blood.

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CROI 2015