Cellular immunity in HIV-1 infection is believed to play a key role in immunopathogenesis, and has become an important focus in vaccine development. Recent technological advances have revolutionized the accuracy and precision of HIV-1-specific CTL detection in infected persons and vaccinees. However, insight into the antiviral function of these cells is not provided by these measures. Basic questions about the interaction of HIV-1-specific CTL with infected cells remain unaddressed by correlative studies in vivo. We have developed in vitro systems to approach experimentally some of these issues. Our studies thus far have indicated that CTL clones vary in their ability to recognized infected cells and inhibit viral replication. Epitope specificity appears to have an important influence on the efficiency of CTL against HIV-1, as well as the ability of the virus to escape from immune pressure. These issues have potentially important implications in the immunopathogenesis of infection and vaccine development. We propose to pursue further studies of the mechanisms by which CTL targeting influences function. Specifically, we intend: (1) To build panels of CTL clones and target cells for further functional studies; (2) To evaluate the factors involved in epitope-dependence of efficiency of HIV-1 inhibition by CTL; and (3) To evaluate HIV-1 escape from CTL of varying epitope specificities.
The first Aim will expand the availability of the CTL, including those of previously unavailable specificities(e.g. Tat, Vif), for these studies, utilizing new technologies that markedly increase the efficiency of mapping and isolating CTL. New approaches will also be undertaken to produce HLA matched virus-permissive cell lines, to overcome the other major hurdle in studies of this nature.
The second Aim will evaluate the impact of CTL specificity on antiviral function, including a detailed dissection of viral replicative kinetic events in relation to CTL susceptibility, and examination of protein levels and their impact.
The third Aim will expand studies begun in the last funding period, examining the propensity of HIV-1 to escape from CTL clones, allowing a controlled evaluation of factors that determine the ability of escape to occur, with particular attention to T cell receptor properties of individual clones and epitope specificity.
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