The thymus is the major organ of T cell production and is generally believed to be nonfunctional in adults. Even if present, it is destroyed by HIV-1 infection while, at the same time, T cells are destroyed in the peripheral lymphoid system. Given the absence of de novo T cell production and a pathologic acceleration of T cell destruction, the immune system collapses and immunodeficiency ensues. The experiments of this R01 address the hypothesis that the thymus may be more active in adults with HIV-1 disease than previously assumed. This hypothesis is based on the preliminary observation that abundant thymic tissue is detectable in a surprisingly large fraction (47/99) of HIV-1-seropositive adults, aged 20-59. Independent of age, radiographic demonstration of thymic tissue was significantly associated with both a higher CD4+ T cell count and a higher percentage and absolute number of circulating naive (CD45RA+CD62L+) CD4+ T cells. The prevalence of an abundant thymus was especially high in younger HIV-1-seropositive adults (less than or = 39 years) with CD4 counts in the range of 300-500 cells/mu1 and in older subjects (greater than 40 years) regardless of CD4 count (p=0.03). These studies suggest that the thymus is functional in many adults with HIV-1 disease, and raise the specific hypothesis that thymic function in the adult might be induced as a consequence of HIV-1- mediated peripheral T cell depletion. To test this hypothesis, the following specific aims are proposed: 1. To determine whether the thymus is functional in HIV-1-seropositive adults. 2. To determine whether suppression of viral replication is associated with enhanced thymic function in HIV-1-seropositive adults. 3. To determine whether peripheral feedback may upregulate thymopoiesis in HIV-1 -seropositive adults. The experiments of this R01 are linked scientifically and administratively (through an """"""""Interactive Research Project Grant"""""""") with an R01 submitted by Dr. Marc Hellerstein, entitled """"""""T cell kinetics and sources: effects of HIV and therapy."""""""" This interactive project will address the general hypothesis that T cell dynamics in HIV-1 disease, and hence - the ability to regenerate a functional immune system -- are critically dependent upon the presence or absence of thymic tissue. A """"""""shared resource"""""""" will be required to address this hypothesis, including a fluorescence activated cell sorter maintained under Biosafety Level 3 precautions in Dr. McCune's lab and a mass spectrometer maintained in Dr. Hellerstein's lab.
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