The principle that adoptively transferred T lymphocytes have therapeutic promise for HIV infection is wellestablished. Our long range goals are to establish the safety of infusions of lentiviral engineered T cells, andto test second generation transgenes for safety and improved antiviral efficacy. Our long range objective isto obviate the need to take daily antiviral medications in patients with HIV infection. In a recently completedphase I pilot study, we have demonstrated the safety and feasibility of a single infusion of lentiviralengineered autologous CD4 T cells when administered to HIV infected subjects with late-stage, HAARTresistant HIV infection. To date, there is no evidence of insertional mutagenesis, and one subject hasexperienced a reduction in viral load. The engraftment and persistence of the gene-modified T cells issatisfactory and suggests that the VSV-G pseudotyped HIV-based lentiviral vector system is nonimmunogenic.Based on our previous studies of costimulated CD4 T cells, we now hypothesize that multipleinfusions of lentiviral engineered autologous CD4 T cells that express the VRX496 antisense env transgenewill lead to a sustained and higher level engraftment. We further hypothesize that the transgene will conferantiviral effects. Two clinical trials are proposed to test these hypotheses. First, we will perform a multipledosephase l/ll study in patients whose viral replication is suppressed on HAART. Structured treatmentinterruption will be carried out to assess antiviral efficacy, and lymphoid biopsies will be used to determinetissue trafficking of the engineered CD4 T cells. In trial #2 we will test a lentiviral vector developed in project3 that expresses a more potent antiviral product. We will compare the relative survival of the T cellstransduced with the second generation vector to cells transduced with the original VRX496 vector tested intrial #1. Together, these trials will represent the first formal efficacy tests of lentiviral engineered T cells fortheir potential to serve as a potent antiviral therapy for treatment of HIV-1 infection. This project interactswith projects 2, and 3, and the project relies on Cores A and B for cGMP lentiviral vector manufacturing andfor clinical grade T cell expansion and transduction technology
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