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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01AI043864-05
Application #
6656077
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (02))
Program Officer
Bridges, Sandra H
Project Start
1999-03-01
Project End
2008-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$709,914
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Seu, Lillian; Ortiz, Gabriel M; Burt, Trevor D et al. (2014) Levels of circulating myeloid subpopulations and of heme oxygenase-1 do not predict CD4(+) T cell recovery after the initiation of antiretroviral therapy for HIV disease. AIDS Res Ther 11:27
Emu, Brinda; Moretto, Walter J; Hoh, Rebecca et al. (2014) Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease. PLoS One 9:e85613
Miller, Corey N; Hartigan-O'Connor, Dennis J; Lee, Myeong Sup et al. (2013) IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. Int Immunol 25:471-83
Baum, Paul D; Young, Jennifer J; Schmidt, Diane et al. (2012) Blood T-cell receptor diversity decreases during the course of HIV infection, but the potential for a diverse repertoire persists. Blood 119:3469-77
Baum, Paul D; Young, Jennifer J; McCune, Joseph M (2011) Measurement of absolute T cell receptor rearrangement diversity. J Immunol Methods 368:45-53
Baum, Paul D; Young, Jennifer J; Zhang, Qianjun et al. (2011) Design, construction, and validation of a modular library of sequence diversity standards for polymerase chain reaction. Anal Biochem 411:106-15
Baum, Paul D; Sullam, Paul M; Stoddart, Cheryl A et al. (2011) Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase. AIDS 25:2243-8
Burt, Trevor D; Seu, Lillian; Mold, Jeffrey E et al. (2010) Naive human T cells are activated and proliferate in response to the heme oxygenase-1 inhibitor tin mesoporphyrin. J Immunol 185:5279-88
Stoddart, Cheryl A; Keir, Mary E; McCune, Joseph M (2010) IFN-alpha-induced upregulation of CCR5 leads to expanded HIV tropism in vivo. PLoS Pathog 6:e1000766
Napolitano, Laura A; Schmidt, Diane; Gotway, Michael B et al. (2008) Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 118:1085-98

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