(Taken from Abstract) The dynamics of T lymphocyte populations stand at the center of HIV-1 immunopathogenesis. Direct measurement of T cell proliferation and destruction rates has not previously been possible, however. We recently described a stable isotope/mass spectrometric technique for measuring cell proliferation and turnover rates in humans in vivo (PNAS, January, 1998) and have performed basic studies of T cell kinetics in AIDS. We propose here to investigate in greater detail the kinetics and sources of T lymphocytes and the functional correlates of T cell dynamics in healthy controls and in HIV-1-infected subjects. Two studies are proposed. In protocol (1), HIV-1-seronegative normals (n=20) are compared to HIV-1-infected subjects with CD4 counts between 150-300 cells/mm3, and either low viral load (<10,000 copies/ml, n+10) or high viral load (>50,000 copies/ml, n=10) and to HIV-1 infected subjects receiving highly active anti- retroviral therapy (HAART) with suppression of VL below detection limit for 3-6 months (n=20). The HIV-1 seronegative controls and HAART patients will be stratified based on radiographic evidence of abundant vs non-abundant thymic mass (n=10/group). The absolute proliferation rates and fractional replacement rate constants for CD4+ and CD8+ T cells, both """"""""naive"""""""" (CD45 RA + CD62L+) and """"""""memory (CD45 RA +/-CD62L-) populations, will be measured in vivo by infusion of [6,6-2H2] glucose, isolation of cells by fluorescence activated cell sorting and MS analysis of deoxyribonucleotides from DNA, as described previously. Comparisons include naive vs. memory. CD4+ vs. CD8+, thymic vs. athymic individuals and HIV-1-infected vs. healthy controls. The relationship between naive CD4+ T cell proliferation and Vbeta T cell receptor (TCR) repertoire diversity will also be explored. Protocol (2) examines the effects and time course of highly active anti-retroviral therapy (HAART) on T cell dynamics in AIDS. Patients with and without abundant thymic mass (n=10/group) will be studied before HAART then at 3-6 months and again after 12-18 months of therapy. Changes in naive vs. memory T cell kinetics. Vbeta TCR repertoire diversity, thymic mass, CD4 count and T cell representation will be correlated. T cell kinetics from tonsillar biopsies will also be compared to kinetics of circulating T cells, to establish whether blood T cells reflect tissue kinetics. These studies are proposed as an interactive R01 (IRPG) with Dr. J.M. McCune. In summary, the availability of a technique for direct measurement of T cell dynamics in vivo allows fundamental questions concerning HIV-1 immunopathogenesis to be addressed, focusing on the sources of T cells and the immunologic correlates of T cell dynamics.
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