Pathogenic events resulting from high viral replication during acute HIV infection, and the immune responses to the virus determine the ultimate level of HIV in a patient, and also the emergence of occasional individuals who are able to control HIV without drug therapy. Three interrelated perturbations in normal immunological responses 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 4 examines the effects of high viremia in acute HIV infection on thymic output, whether a decrease in recent thymic emigrants (RTEs) is polyclonal or oligoclonal, and the relative contributions to the distortion and loss of diversity of the TCR repertoire, and the loss of HIV-specific CD4 cells (projects 1 and 3) of a) large numbers of CD4 cells entering cell cycle, b) decreased RTEs and c) the effects of decreased TCR alpha chains on beta-alpha chain pairing. The effects of antiretroviral therapy in partially reversing these abnormalities also will be studied. RTEs will be identified by a unique surface phenotype as assessed by multicolor flowcytometry and by the alpha/beta TREC ratio that is influenced by intrathymic proliferation but not by peripheral dilution. The hypothesis will be examined that an HIV-initiated large increase in the production of interferon-alpha by the plasmacytoid DC (in collaboration with project 2) is responsible for the decrease in intrathymic proliferation.
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