1003. HIV-1-Derived Lentivirus Vector-Based Antisense Gene Therapy: Towards an Alternative Treatment for HIV/AIDS
Authors: Boro Dropulic, Laurent Humeau, Gwendolyn K. Binder, Xiaobin Lu, Vladimir Slepushkin, Randall Merling, Patricia Echeagaray, Mario Pereira, Tatiana Slepushkina, Scott Barnett, Lesia K. Dropulic, Richard Carroll, Bruce Levine, Rob Roy MacGregor, Carl H. June
Journal: Molecular Therapy (2004)

Despite the significant advancement in HIV/AIDS treatment with highly active antiretroviral therapy (HAART), HIV/AIDS remains incurable. Limitations of HAART include expense, disabling complications, and a stringent requirement for compliance. In the United States, where HAART has become the standard of care, approximately 20% of newly transmitted virus is already resistant to at least one antiretroviral drug. In anticipation of expanded HAART in Africa, there is concern regarding rapid emergence of drug resistant strains of HIV that brings into question HAART as a long-term solution. We have developed an alternative therapy for HIV/AIDS therapy using an HIV-1-based lentiviral vector expressing a 937-base antisense gene against the HIV envelope, VRX496, for autologous T cell therapy. T cells are transduced with vector in the presence of co-stimulatory CD3/CD28 beads, and subsequently expanded in culture. Preclinical studies demonstrated the feasibility of this approach in normal CD4+ T cells and inCD4+ T cells isolated from 20 early and late stage patients, as defined by viral loads. An efficient gene transfer procedure was established, which demonstrated stable transfer rates of 94% +/- 5%. Antisense inhibited HIV in cultures by >93% over mock transduced controls, regardless of patient status or the tropism of the infecting virus. A Phase I open label non-randomized clinical trial was then initiated to investigate the safety and tolerability of autologous T cells modified with VRX496. In this study, 5 HAART resistant patients having CD4 T cells counts between 200-500 cells/mm3 are serially enrolled in the study that includes 3-week, and 3 and 6-month monitoring points. Each patient is given approximately 1 1010 modified autologous CD4 T cells in a single dose. Patients are monitored for viral load, CD4 count, emergence of any replication competent lentivirus (RCL), immunological parameters, and clinical indications. Adverse events are defined in part by a sustained 0.5 log increase in viral load, or sustained 0.5 log decrease in CD4 count within 3 weeks post dose. To date, 3 subjects have been infused, and the first and second subjects have completed the 6 and 3-month monitoring points, respectively. No adverse events have been noted, and all RCL assays have been negative. CD4 counts remained steady and engraftment of VRX496-modified cells was observed for at least 6 months in the first patient and 3 months in the second patient. At dosing, subject 1 had an average viral load of 188,500 and subject 2 had an average viral load of 40,428. After three and six months post dosing, subjects 1 and 2 respectively, had viral loads below baseline. This interim analysis supports the promise of lentiviral vectors for late stage HIV infection, and that VRX496 could become a viable treatment modality for individuals infected with HIV/AIDS.