Background:  HAART has offered hope to many HIV patients in the developed world, but the cost, side effects, and dosing regimen reduce patients’ quality of life. Additionally, emerging drug resistance raises concerns about HAART as a long-term therapy.

Methods:  We have developed an HIV-1-based lentiviral vector expressing a 937-base antisense gene against the HIV envelope for autologous T-cell therapy for HIV/AIDS. The vector introduces no new sequences to an HIV-infected individual. In preclinical studies, HIV replication was inhibited more than 95%, and as much as 4 logs, in primary CD4 T lymphocytes isolated from HIV-infected patients. For evaluation of safety and tolerability of this therapy, a phase I open-label non-randomized clinical trial has been carried out.  Five patients who have failed at least 2 HAART regimens because of intolerance or resistance, and have CD4 counts above 150 cells/mm³ and a viral load ≥ 5000 copies/mL, have been serially enrolled for a 6-month study with 1-, 2-, 3-, and 6-week, and 3- and 6-month monitoring points. Each patient was given a single intravenous dose of ~ 1 x 10¹⁰ modified autologous T cells, and then monitored for viral load, CD4 count, replication competent lentivirus (RCL), outgrowth of vector-modified cells, immunological parameters, and adverse events.

Results:  Serious adverse events were defined in part by a sustained 30% increase in viral load, or sustained 0.5 log decrease in CD4 count within 3 weeks post dose. All 5 patients have been dosed, and 4 have completed the critical 3-week safety time-point. No serious adverse events have occurred, and all RCL tests have been negative, including a biological RCL assay performed on apheresed patient peripheral blood mononuclear cells (PBMC) at 6 months. Patients have, respectively, completed their 1-year, 9-, 6-, and 3-month, and 2-week monitoring time-points. CD4 counts remained steady in all patients. The first 2 patients exhibit viral loads below baseline, while the second 2 patients maintain baseline viral loads. Circulating VRX496-modified cells were detected in 2 of 2 patients until 9 months post dosing. To date, 211 integration sites from 5 transduced clinical products have been analyzed; initial results indicate that VRX496 preferentially integrates into transcription units and disfavors integration into alphoid repeats, a pattern that is comparable to and indistinguishable from wild type HIV.

Conclusions:  Together, these data support the safety and feasibility of lentiviral vector therapy in the setting of ex vivo cellular therapy.

Keywords: HIV; Lentiviral Vector; Gene Therapy