Over a decade after the identification of HIV as a human pathogen, the correlates of protective immunity in this infection are yet to be determined, and an effective vaccine remains an elusive goal. The demonstration that high levels of viremia drop rapidly during primary HIV infection provides strong support that antiviral immune responses are an important protective host defense, and emerging data suggest that virus-specific CTL may play a key role in this process. However, the precise mechanism(s) by which these cells may contribute to control of infection remains unclear, and the potential role of sequence variation in contributing to disease progression, either through escape from established responses or through antagonism, is not established. CD8 cells from infected persons have been shown to produce a soluble factor which inhibits HIV-1 replication by a non-cytolytic mechanism, and recent data indicate that beta-chemokines and IL-16 may contribute to the observed suppression. However, the potential relationship between the CD8 inhibitory cells and CTL remains obscure, and no studies have identified the factors which trigger the release of the soluble inhibitory factors. The purpose of this competing renewal is to continue to perform a detailed analysis of the ability of CTL to inhibit viral replication, and to determine the role of virus-specific CTL in the observed inhibition mediated by CD8 cells. In addition, the contribution of sequence variation to escape from cellular immune effector mechanisms will be assessed. Virus-specific CTL clones of known epitope-specificity and HLA restriction, as well as CD8 cells from infected persons, will be used in a novel and precisely defined system developed during the previous funding period in which the target cells, effector cells and infecting inoculum can be manipulated in a highly reproducible fashion. These studies in a system in which confounding variables can be controlled should help to clarify the role of CTL and soluble factors released by CD8 cells in HIV-1 infection. Specifically, the P.I. proposes to a) determine the ability of HIV-1-specific CTL clones to structural and non-structural viral proteins to inhibit HIV-1 replication b) determine the effects of sequence variation on the ability of clones to inhibit HIV-1 replication, c) determine the relative contributions of cell killing versus release of soluble factors in inhibiting viral replication, and d) identify the soluble factor(s) released from HIV-1-specific CTL clones and CD8 cells which inhibit HIV-1 replication.
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