The broad long-term objective of this proposal is to determine the contribution of CD8 T cells to the outcome of chronic HIV-1 (HIV) disease. This knowledge will provide a better understanding of the mechanisms involved in viral clearance. The hypothesis is that CD8 T cell immunity determines the outcome of HIV disease.
The specific aims are to: 1) Determine which CD8 mediated functions are present in patients at various stages of HIV disease; 2) Determine whether certain CD8 cell functions are indicators of prognosis; 3) Determine through phenotypic analysis whether functionally distinct populations mediate these activities; and 4) Determine whether loss of CD8 cell function in late HIV disease is due to loss of the phenotypically defined subsets of cells that mediate these activities. CD8 cells and CD8 subsets obtained by dual- or three-color fluorescence activated cell sorting (FACS) will be tested for several CD8 mediated activities: anti-HIV MHC class I restricted cytotoxicity using EBV-transformed lymphoblast targets that are infected with vaccinia virus-HIV recombinants or coated with synthetic HIV peptides; anti-HIV activity manifest as suppression of endogenous HIV replication from autologous activated CD4 cells; non-HIV directed killing of autologous CD4 cells; """"""""redirected"""""""" killing in the presence of anti-CD3 and; mitogenicity to anti-CD3. The relationship of these CD8 functions to disease status (which will be evaluated by CD4 number and viral load) will be determined. Longitudinal testing and long-term follow-up of the patients will permit the elucidation of the role that these CD8 functions play in determining disease progression. The project will provide information on the role of CD8 cells in control of chronic HIV disease, lead to better ways of assessing cellular immune response to HIV vaccines, and provide information on whether CD8 immunotherapy may lead to viral clearance in HIV infected hosts.
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