HIV-specific CD8+ CTL responses are strongly implicated in the control of HIV infection. However, these CTL responses eventually decline during disease progression and viral control is lost. Therapeutic strategies to augment the partially effective host HIV-specific CD8+ CTL response may be efficacious in regaining control of HIV. In conjunction with others in the laboratory, I have evaluated adoptive immunotherapy of HIV infection with in vitro expanded, autologous, gene-modified HIV- specific CD8+ CTL clones to enhance the efficacy of the CTL response. The effectiveness of this initial therapy was limited because of shortened survival of the transferred CTL likely due in part to insufficient T-helper function present in these HIV+ individuals. T- helper function could potentially be restored by intravenous infusions of IL-2, or by the transfer of autologous HIV-specific CD4+ T helper (Th) clones. The survival of transferred CD4+ Th clones would likely be improved by genetic modification to express IC-imm genes, which render cells resistant to replication of HIV by interfering with critical steps in the viral life cycle. Building on previous trials, we plan to evaluate adoptive immunotherapy of HIV infection with CD8+ CTL provided with T helper activity. In this application, I propose to extend my previous studies and perform immunologic and virologic analyses of this trial to evaluate the anti-viral effect and potential reasons for efficacy limitations of adoptive immunotherapy for HIV.
The specific aims are: To evaluate in HIV+ individuals immunotherapy for HIV with in vitro-expanded, autologous, neo-marked Gag-specific CD8+ CTL clones, supplemented by intravenous infusions of IL-2 or supplemented by the transfer of HIV-specific CD4+ Th clones expressing IC-imm genes; and to determine if the transfer of HIV-specific CD4+ Th clones expressing IC-imm genes alone will augment HIV-specific immunity. Studies will determine if these interventions promote the persistence, in vivo expansion, and function of the transferred cells and evaluate if limitations of efficacy result from the selection of HIV variants with mutation of the HIV epitopes recognized by transferred cells. I have chosen to pursue my research in Dr. Philip Greenberg's laboratory at the FHCRC because I feel that it offers an outstanding and unique environment in which study host defense to viral pathogens. My primary goal in working in this laboratory is to apply techniques of modern T cell immunology to studying host defense to HIV. My long-term goal is to work in an academic medical center as a physician scientist with a primary focus on the immunopathogenesis of HIV infection.
| Lewinsohn, David M; Tydeman, Ian S; Frieder, Marisa et al. (2006) High resolution radiographic and fine immunologic definition of TB disease progression in the rhesus macaque. Microbes Infect 8:2587-98 |
| Lewinsohn, Deborah A; Heinzel, Amy S; Gardner, James M et al. (2003) Mycobacterium tuberculosis-specific CD8+ T cells preferentially recognize heavily infected cells. Am J Respir Crit Care Med 168:1346-52 |
| Lewinsohn, Deborah A; Lines, Rebecca; Lewinsohn, David M et al. (2002) HIV-1 Vpr does not inhibit CTL-mediated apoptosis of HIV-1 infected cells. Virology 294:13-21 |
| Lewinsohn, Deborah A; Lines, Rebecca A; Lewinsohn, David M (2002) Human dendritic cells presenting adenovirally expressed antigen elicit Mycobacterium tuberculosis--specific CD8+ T cells. Am J Respir Crit Care Med 166:843-8 |
