The first submission of this R01 (AI43864-01, 3/01/99-2/28/03) addressed the hypothesis that thymic function in the adult might be induced as a consequence of HIV-mediated peripheral T cell depletion. Studies funded by the grant have to date generated 11 peer-reviewed publications (ref. # 1-11) and 7 additional manuscripts have been submitted (ref. # 12,13) or are in preparation (ref. # 14-18) These manuscripts detail findings which indicate that thymic function can be observed in many adults with HIV disease, that such function may be induced by positive feedback regulation of T cell production, and that the presence or absence of such function may play a determinant role in disease progression and response to highly active antiretroviral therapy (HAART). These observations suggest that T cell depletion can induce the secretion of positive regulators of T cell production. 19 We now wish to extend and to elaborate upon these findings. In particular, we will determine whether true thymic function can be induced in HIV-infected adults, whether such induction is indeed prompted by de novo production of positive feedback regulators, and whether thymic function plays a role in sustaining the T cell compartment in the face of peripheral T cell depletion. The following specific aims will be pursued: (1) to determine whether administration of GH to HIV-infected patients on HAART facilitates the generation of long-lived naive T cells with a diverse TCR repertoire; (2) to determine whether specialized cells express IL-7de novo in response to peripheral T cell depletion; and (3) to determine the relative contribution of thymic function to the maintenance of the naive T cell compartment in the setting of chronic antigenic stimulation. As detailed in section (i), the experiments of this R01 have been and will continue to be linked scientifically and administratively (through an """"""""Interactive Research Project Grant,"""""""" or IRPG) with an R01 submitted by Dr. Marc Hellerstein, entitled """"""""T cell kinetics and sources - effects of HIV and therapy."""""""" These two R01s will share a Core that enables a novel approach (using metabolic labeling with deuterated glucose or deuterated water) for studying the kinetics of turnover of various T cell subpopulations in humans. The specific hypotheses to be tested in this IRPG are: (1) that GH administration to HIV-infected adults on HAART will augment the generation of naive phenotype T cells with a long half-life; and (2) that T cell depletion in persistently-stimulated D011.10 TCR transgenic mice will alter the kinetics of naive T cell production.
Showing the most recent 10 out of 21 publications
