The goal of this proposal is to study the contribution of the thymus to the pathogenesis of SIV infection in rhesus macaques. The first approach to be used is primarily based upon our recently developed technique to quantify the number of recent thymic emigrants (RTE) in blood by measuring a major excisional DNA byproduct (termed alpha1 circle) of T-cell receptor (TCR) rearrangement. By monitoring the decay of alpha1 circle concentration in the peripheral blood following surgical removal of the thymus (thymectomy), the intrinsic thymic output can be calculated. The second approach will be to in situ label thymocytes by injection of the thymus with a fluorescent dye CFSE, and to follow the fluorescent-labeled RTE in the peripheral blood. These two different approaches will provide a genetic and cellular marker for the RTE, so that the intrinsic thymic output can be accurately estimated. The impact of SIV infection on the thymic output will also be studied by comparing the alpha1 circle concentration before and after SIV infection. In addition, thymic contribution to peripheral T lymphocyte dynamics will be analyzed by sequential measurement of the alpha1 circle concentration in various cell populations, in particular in the naive and memory cells. The regenerative capacity of the thymus will be further studied by measuring the changes of the alpha1 circle in the blood after infected animals are treated with the antiretroviral drug PMPA. The source and mechanism of the increase in T cells following antiretroviral treatment will then be addressed by comparing the surface phenotypes of lymphocytes and alpha1 circle numbers before and after treatment. The information from the proposed studies will contribute to our understanding of HIV-1 pathogenesis, in particular the role of the thymus in the regeneration of T lymphocytes during the course of infection and after treatment with highly active antiretroviral therapy (HAART).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046964-02
Application #
6374415
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Wassef, Nabila M
Project Start
2000-07-15
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$466,953
Indirect Cost
Name
Aaron Diamond AIDS Research Center
Department
Type
DUNS #
786658872
City
New York
State
NY
Country
United States
Zip Code
10016
Chen, Hannah Yuan; Di Mascio, Michele; Perelson, Alan S et al. (2007) Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques. Proc Natl Acad Sci U S A 104:19079-84
Fernandez, Sonia; Nolan, Richard C; Price, Patricia et al. (2006) Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy. AIDS Res Hum Retroviruses 22:163-70
Lin, Hsi-Hsun; Gaschen, Brian K; Collie, Mary et al. (2006) Genetic characterization of diverse HIV-1 strains in an immigrant population living in New York City. J Acquir Immune Defic Syndr 41:399-404
Arron, Sarah Tuttleton; Ribeiro, Ruy M; Gettie, Agegnehu et al. (2005) Impact of thymectomy on the peripheral T cell pool in rhesus macaques before and after infection with simian immunodeficiency virus. Eur J Immunol 35:46-55
Mehandru, Saurabh; Poles, Michael A; Tenner-Racz, Klara et al. (2004) Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200:761-70
Poles, Michael A; Barsoum, Shady; Yu, Wenjie et al. (2003) Human immunodeficiency virus type 1 induces persistent changes in mucosal and blood gammadelta T cells despite suppressive therapy. J Virol 77:10456-67
Zhang, Linqi; Rowe, Leslie; He, Tian et al. (2002) Compartmentalization of surface envelope glycoprotein of human immunodeficiency virus type 1 during acute and chronic infection. J Virol 76:9465-73
Zhang, Linqi; Dailey, Peter J; Gettie, Agegnehu et al. (2002) The liver is a major organ for clearing simian immunodeficiency virus in rhesus monkeys. J Virol 76:5271-3
Hong, R; Shen, V; Rooney, C et al. (2001) Correction of DiGeorge anomaly with EBV-induced lymphoma by transplantation of organ-cultured thymus and Epstein-Barr-specific cytotoxic T lymphocytes. Clin Immunol 98:54-61