The proposed studies will continue the examination and characterization of HIV-1 specific cytotoxic T cell responses in adult human recipients of vector-based vaccines.
Specific aims of the proposal are: 1) To carry out longitudinal studies defining the human CTL response to candidate AIDS vaccines focusing on the breadth and duration of responses induced by the replication-defective viral vectors that are being considered for use in the Phase III clinical trials. 2) To isolate vaccine-induced CTL clones which will be characterized with respect to phenotype, MHC restriction, epitope specificity, cross-reactivity on diverse HIV-1 isolates, lysis of HIV-1 infected cells, and production of cytokines and chemokines. 3) To examine the factors responsible for the absence of CTL responses in some vaccines. 4) To determine the conditions under which HIV-1 infected CD4 T cells in the pre- and post-integration states of latency are susceptible to lysis by vaccine-induced, HIV-1-specific CTL. To address these specific aims, the proposing investigators will serially screen for HIV-1 specific CTL in the blood of vaccine recipients using a sensitive virus-specific stimulation technique they developed during the initial funding period. CTL clones will be derived from the bulk cultures generated to screen for vaccine-induced CTL activity and will be functionally characterized. Vaccine recipients without detectable CTL responses will be characterized with respect to other immunologic responses (antibodies, lymphoproliferative responses) to vaccine antigens. Those with detectable antibody or T cell proliferative responses will be studied to determine whether CTL non-responsiveness is MHC related by screening HIV-1 infected individuals matched at individual MHC loci for CTL reactivity. Alternatively, in vitro stimulation with defined optimal peptidic epitopes will be used to better distinguish vaccines responders vs. nonresponders. Antigen processing and presentation will then be studied using cells from non-responders. Finally the ability of HIV-1 specific CTL to lyse newly or chronically infected resting CD4 T cells will be examined.
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