This is a competing renewal application to characterize the evolution, selection and pathogenesis of M-tropic versus T-tropic variants of HIV-1 in the host, and examine the genetic, phenotypic, biochemical and immunological changes in viruses that are selected over the course of infection and progression to AIDS. To do this, the Principal Investigator proposes to: (1) define the pathogenesis of SIV variants that evolve with the development of AIDS, including the pathogenesis of a T-tropic, syncytia-inducing blood-derived variant and lymph node variant cloned directly from macaque with AIDS; (2) define the role of viral tropism and co-receptor specificity in virus replication and pathogenicity of SIV and HIV; (3) characterize viral variation, viral phenotype, antibody epitopes and co-receptor utilization in a well-defined cohort of rapid progressor, progressor, and non-progressor macaques; and (4) determine whether glycosylation changes in HIV-1 envelope protein enable the virus to escape neutralizing antibody recognition. The scope of the proposed studies will include analysis of molecular, biological, and immunological properties of the variants selected in the host, and characterization of related virus-host interactions during persistent infection. The expectation is that knowledge gained will provide insight into the mechanisms underlying progression to AIDS.
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