Clearance of the very high levels of plasma viremia that generally accompany acute infection with HIV is a consequence of host immune responses to the virus. Despite this ability of the immune system to mediate a profound decline in viral burden, HIV eventually evades immunologic control. CD4+ T helper responses have been shown to be necessary for containment of chronic viral infections, and one hallmark of HIV infection is the deficiency from very early in disease of a substantial CD4+ T cell response to the virus. Thus, strategies to correct this deficiency, particularly if combined with new antiretroviral drug therapies, might result in improved control of HIV. Our laboratory has developed methods to isolate, clone, and expand virus-specific CD4+ T cells in vitro, and has demonstrated that adoptive transfer of such T cells can reconstitute deficient CD4+ T cell responses in vivo. There are several obstacles to applying this technology to the treatment of HIV-- most significantly, transferred HIV-specific CD4+ T cells would likely localize to sites of infection and be at risk for rapid deletion. Therefore, methods are being explored to modify these cells prior to infusion by the introduction of genes that render them resistant to HIV infection, a technique termed intracellular immunization (IC-imm). The administration to HIV-infected individuals of large numbers of such autologous, protected, HIV-specific CD4+ T cells should provide a unique opportunity to assess the impact of a competent immune response on HIV. The proposed studies include preclinical experiments to develop improved molecular strategies to protect CD4+ T cells from infection by HIV, and clinical trials to determine the in vivo biologic activity of CD4+ T cells expressing these genes.
The specific aims are to: (1) evaluate in vitro the ability of IC-imm genes designed to prevent infection to preserve the survival and function of HIV-specific CD4+ T cells exposed to infectious HIV and to compare this antiviral activity with IC-imm genes designed to inhabit viral replication; (2) evaluate the ability of IC-imm genes to protect and preserve the function of adoptive transferred HIV-specific CD4+ T cells in patients with CD4+ counts greater than 200 and with greater than 1000 copies of HIV/ml; (3) evaluate the ability of adoptively-transferred gp-160-specific CD4+ T cell clones expressing IC- imm genes to persist and modulate antiviral immunity in individuals on anti-retroviral therapy with CD4+ counts greater than 200 and plasma viremia between 50 and 500 copies of HIV/ml; and (4) determine if the transfer of HIV-specific CD4+ T cells resistant to HIV and of HIV-specific CD8+ CTL in patients with primary HIV infection can provide persistent cellular immunity to HIV.
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