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T-Cell Homeostasis and CD8 Responses Predict Viral Control Post SB-728-T Treatment
Joumana Zeidan1; Gary K. Lee2; Clarisse Benne1; Slim Fourati1; Shelley K. Wang2; Jacob Lalezari3; Gary Blick4; Geoffrey M. Nichol2; Dale K. Ando2;Rafick Sekaly1
1Case Western Reserve Univ, Cleveland, OH, USA;2Sangamo BioSciences, Richmond, CA, USA;3Quest Clinical Rsr, San Francisco, CA, USA;4CIRCLE CARE Cntr, Norwalk, CT, USA
Infusion of ZFN driven CCR5 modified T-cells (SB-728-T) in HIV infected subjects was previously shown to durably improve CD4 counts. Long-term CD4 reconstitution and decay of the HIV reservoir were previously correlated with a novel memory stem cell (TSCM) CD4 subset that expands post-infusion and is enriched in CCR5-modified cells. This current study aims at identifying correlates and mechanisms that lead to control of viremia post treatment interruption (TI).
18 ART treated subjects with CD4 counts above 500 were preconditioned with 0.1-2.0 g/m2 of Cytoxan prior to infusion of SB-728-T. Subjects initiated TI at 6 weeks post infusion. T cell count and viral load (VL) were monitored regularly for 12 months following treatment. Immunologic and viral analyses (immuno-phenotyping, reservoir analyses, anti-HIVgag effector functions, etc) were performed at selected time points.
Of the 9 subjects pre-conditioned with Cytoxan doses of 1.0 and 1.5 g/m2, 6 subjects demonstrated durable control of viremia (VL<10,000) in extended TI (duration= 14-26 months), with 2 subjects showing consistent ongoing VL measurements <1000 (duration= 17 & 20 months). Using a univariate linear regression model, greater levels of CCR5 modified cells before TI (p=0.03) and frequencies of CD4 TSCM during TI (p=0.01) correlated with lower VL, suggesting that greater levels of the HIV resistant T-cell compartment could be critical in conferring post-treatment control possibly by restoring immune homeostasis and providing help to HIV specific CD8 T cells. Multivariate analyses were used to determine parameters that further predict viremia control during TI. Results indicate that higher CD4 TSCM levels, along with greater polyfunctional anti-HIV gag CD8 response during TI (p=0.04) were associated with reduced viral load. Further, HIV reservoir size prior to TI showed a significant interaction with CD8 response in this model (p=0.03), suggesting that greater HIV reservoir were associated to HIV specific CD8 responses that failed to control virus upon TI.
Control of viremia during treatment interruption was demonstrated in 6 subjects treated with CCR5 modified T-cells. In a multivariate model, data from immunologic and reservoir analyses suggest that the best predictors for post treatment viral control are restored T cell homeostasis as suggested from greater levels of SB-728-T engraftment, polyfunctional antiviral CD8 responses during TI and lower HIV reservoir levels prior to TI.