Abstract Body

Background: The E.coli-derived MazF endoribonuclease specifically cleaves single stranded RNAs at ACA sequences. HIV-1 contains over 240 ACA sequences, making it especially sensitive to MazF activity. In this study, autologous CD4+ T cells are modified using a retroviral vector containing the mazF gene expressed under the control of the HIV LTR. MazF expression is thus activated by Tat conditionally during HIV replication. This study is designed to evaluate the safety and durability of MazF-modified CD4+ T (MazF-T) cells, and assess related antiviral effects.

Methods: This is an exploratory Phase I, Open Label, Dual Cohort study evaluating safety, tolerability and immunogenicity of autologous CD4+ T cells expressing the MazF endoribonuclease gene in HIV+ subjects. Both cohorts consist of subjects on combination antiretroviral therapy (cART) with CD4 counts >350 cells/mm3 and undetectable HIV-1 RNA levels. Subjects in cohort 1 remain on cART throughout the duration of the study. Subjects in cohort 2 participate in a 16 week analytical treatment interruption (ATI) beginning 2 weeks post T cell infusion. All subjects are infused with a single dose of MazF-T cells and are evaluated for persistence of modified cells, impact on CD4 count and effects on HIV viral load.

Results: To date, 4 subjects in cohort 1 have each received a single infusion of 0.5-1×1010 cells. There have been no SAE related to MazF-T. All 8 AE related to study drug have been grade 1 in severity. The CD4/CD8 ratio increased in 3 of 4 subjects post infusion, before stabilizing near baseline. Absolute CD4 count remained stable, or slightly increased as compared to baseline. As these subjects remained on cART, all viral loads remained undetectable. MazF DNA signal was detected by qPCR in all 4 subjects’ peripheral blood at the most recently available timepoint, including 2 subjects who completed the study at Day 180.

Conclusions: These preliminary results suggest that autologous MazF-modified CD4+ T cells are safe and well-tolerated in aviremic HIV+ subjects and are able to persist out to 6 months post-infusion. Future results in subjects participating in an ATI will further elucidate the anti-HIV effects associated with MazF-T cells in the presence of viremia.