This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: The evidence leaves little doubt that the Nef protein is a major determinant of AIDS disease progression caused by HIV and SIV. We have shown that soluble HIV-1, -2, and SIV Nef proteins, alone, can cause cell death in CD4+ T cells. We have identified the specific region of the Nef protein, Nef M1, responsible for cell death. We have developed a mouse model to study Nef protein-induced T-cell depletion which is a hallmark of AIDS. In that model we observed cell death in the thymus and spleen, as well as T-cell depletion in the peripheral blood of Nef M1-treated mice. These effects can be blocked by pre-immunizing the mice against the Nef M1 peptide which raises an immune response to that peptide in those mice. This raises the potential for development of therapeutics targeting the Nef apoptotic motif (M1) or the effects of this epitope, which would block Nef-driven T-cell depletion, and prolong, or possibly halt progression towards AIDS in humans. We plan to demonstrate T-cell depletion similar to that observed in mice using soluble Nef-derived M1 peptide in primates.
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