During the natural history of HIV-1 infections there are CD4+ and CD8+ T cell responses by the host to the antigens of the virus. Although these immune responses may help restrict the virus, they are unable to eliminate HIV-1 from the infected individuals. Eventually the host is unable to respond with an effective immune response to numerous organisms and a fatal outcome results from HIV-1 infection. The reasons for the failure of the T cell mediated immune responses to control and eliminate HIV-1 infection need to be studied. We will define CD8+ and CD4+ CTL epitopes and CD4+ T helper epitopes on autologous HIV-1 p24 and gp41 proteins infected individuals. We and others have defined some CD8+ CTL epitopes on HIV-1 but all of us have relied on screening with recombinant vaccinia viruses expressing prototype HIV-1 genes derived from the IIIB, strain or with synthetic peptides based on IIIB sequences. This, the CD8+ T cell epitopes which have been defined are conserved on IIIB. There is much less information available concerning the CD4+ CTL or CD+ T helper epitopes on HIV-1 and this very limited data suffers from the same selection bias because it is based on IIIB reagents. Our strategy is to define autologous T cell responses on p24 and gp41. We will annually isolate fragments of HIV-1 p 24 and gp41 cDNA directly from PBMC or serum by PCR to eliminate in vitro culture selection effects. We will then express these molecular clones of autologous HIV-1 genes in vaccinia to use in assays to identify autologous T cell epitopes using T cell clones generated from the same donor. We will focus efforts on p24 an gp41 sequences generated annually from several HIV-1 infected donors whose T cells will also be cloned annually. We will determine whether antigenic stability, loss or change occurs at CD8+ or CD4+ CTL or CD4+ T helper epitopes; and whether novel HIV-1 specific epitopes emerge at sites outside of previously defined epitopes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS and Related Research Study Section 1 (ARRA)
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University of Massachusetts Medical School Worcester
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