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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043864-04
Application #
6511075
Study Section
Special Emphasis Panel (ZRG5-AARR-2 (01))
Program Officer
Bridges, Sandra H
Project Start
1999-03-01
Project End
2003-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$427,501
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
047120084
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Ladell, Kristin; Hazenberg, Mette D; Fitch, Mark et al. (2015) Continuous Antigenic Stimulation of DO11.10 TCR Transgenic Mice in the Presence or Absence of IL-1?: Possible Implications for Mechanisms of T Cell Depletion in HIV Disease. J Immunol 195:4096-105
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
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
Emu, Brinda; Sinclair, Elizabeth; Hatano, Hiroyu et al. (2008) HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control. J Virol 82:5398-407
Baum, Paul D; McCune, Joseph M (2006) Direct measurement of T-cell receptor repertoire diversity with AmpliCot. Nat Methods 3:895-901
Harris, Jeffrey M; Hazenberg, Mette D; Poulin, Jean-Francois et al. (2005) Multiparameter evaluation of human thymic function: interpretations and caveats. Clin Immunol 115:138-46
Napolitano, Laura A; Burt, Trevor D; Bacchetti, Peter et al. (2005) Increased circulating interleukin-7 levels in HIV-1-infected women. J Acquir Immune Defic Syndr 40:581-4
Hanley, Mary B; Napolitano, Laura A; McCune, Joseph M (2005) Growth hormone-induced stimulation of multilineage human hematopoiesis. Stem Cells 23:1170-9
Hellerstein, Marc K; Hoh, Rebecca A; Hanley, Mary Beth et al. (2003) Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest 112:956-66
Deeks, Steven G; Hoh, Rebecca; Grant, Robert M et al. (2002) CD4+ T cell kinetics and activation in human immunodeficiency virus-infected patients who remain viremic despite long-term treatment with protease inhibitor-based therapy. J Infect Dis 185:315-23

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