Background:  OZ1 comprises a Moloney murine leukemia, replication-incompetent retroviral vector with a tat/vpr specific anti-HIV ribozyme. In this study, the largest randomized, double-blind, placebo-controlled, phase II cell-delivered gene transfer clinical trial, we assessed the safety and efficacy of OZ1 delivered in autologous CD34⁺ hematopoietic progenitor cells.

Methods:  We administered an infusion of CD34+ cells transduced with OZ1 or treated with medium alone to 74 HIV-1⁺ adults. Over 100 weeks, ART was interrupted twice (at weeks 24 to 28 and 40 to 100) to provide positive selective pressure for the progeny of OZ1-transduced CD34⁺ cells. The primary end-point was viral load at weeks 47/48. Secondary endpoints included time-weighted area under the log HIV viral load curve (TWAUC), safety (including those specific to gene transfer studies), T lymphocyte counts, and cell marking.

Results:  No adverse event was attributed to OZ1. The primary endpoint was not met but several other viral load parameters were significantly different in the OZ1 group including: the TWAUC, log₁₀ copies/mL/day for weeks 40 to 48 and weeks 40 to 100; median difference log₁₀ –0.34 (p = 0.024) and –0.37 (p = 0.034), respectively; the number of participants with plasma viral load <4 log₁₀ copies/mL at weeks 47/48 (15 of 32 vs 5 of 33; p = 0.009); the number of participants with a TWAUC in the lowest quartile for weeks 40 to 100 (12 vs 5, p = 0.04) and the median time to increase to 4log₁₀ viral load copies/mL after interruption. In those participants with OZ1 expression beyond week 48, the weeks 47/48 viral load (p = 0.003) and median TWAUC for both weeks 40 to 48 and weeks 40 to 100; p = 0.03 and 0.005, respectively) were significantly lower than in controls. Peripheral blood lymphodepletion related to mobilization and large-volume apheresis occurred in both groups. While not statistically significant, the OZ1 group had higher CD4⁺ T lymphocyte counts (e.g., 476 vs 437 cells/mm³ at weeks 47/48), higher CD4 percentage, and lower CD8 percentage over time. No evidence of resistance to OZ1 or to patients’ ART was seen. No evidence of insertional mutagenesis was detected.

Conclusion:  This study provides the first indication that cell-delivered gene transfer is active in the setting of HIV infection. This type of therapy can reduce HIV viral load, and may preserve immune function and avoid the toxicities associated with antiretroviral therapy.