Immune responses and pathogenic events resulting from high viral replication during acute HIV infection determine the levels of HIV in late infections, and effect or control the emergence of occasional individuals who are able to control HIV without drug therapy. Observations that the initiation of antiretroviral therapy (ART) during acute infection may permit patients to subsequently control HIV without ART also indicate that critical pathogenic events are operative during acute infection. These events include impaired development of HIV-specific CD4 cells, defective antigen presentation, and hyperactivation of T cells with disruptions in T cell production and turnover. Project 3 examines the immunopathology of CD4 cell failure at the clonal level in a selected group of intensively studied subjects, through the use of class II tetramers, and an analysis of functional responses to HIV peptide matrixes as measured by intracellular cytokine production, ELISPOT, and peptide-stimulated lymphocyte proliferation. The experiments also will incorporate measurements obtained in patients participating in project 1. We will determine whether clones are deleted, rendered anergic or only partially responsive, and whether they are entering an apoptosis pathway. This project will also explore the inhibition of CD4 responses to HIV envelope by antibodies to gp120, the specificity of escape from neutralizing antibody in early infection, and whether this escape is influenced by the presence of functional HIV-specific CD4 cells.
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