Since loss of CD4 positive cells is the hallmark of disease progression in HIV infection, understanding the interaction between HIV and the developing T cells in the thymus is crucial for gaining better insight into disease progression. The thymus is essential for normal T cell development and consists of predominantly CD4 positive immature T cell which as we and others have shown can be readily infected with HIV in vitro and in vivo. A productive HIV infection depends on virus strain and on the activation state of the target cell. Our hypotheses are; 1) that thymocyte subsets which are activated and/or proliferating are principle targets for HIV infection; 2) that cytopathic viral strains affect thymocytes at an earlier stage of maturation than non-cytopathic strains and 3) that depletion of thymocytes which produce IFN-gamma results in increased HIV expression by thymocytes and contributes to immunodeficiency. We have an unique opportunity to test these hypotheses using clinical viral isolates in a three-dimensional model comprised of in vitro thymocyte suspension culture, thymus organ culture and thymus grafts in the SCID/hu mouse. The following is an outline of our experimental strategy. We will test which thymocyte subsets are infected and expressing virus y sorting of immature and mature thymocytes subsets after in vitro and in vivo (SCID/hu mouse) infection of thymocytes with isolates of different pathogenicity. In addition, we will compare the functions of HIV-infected with sham-infected thymocyte subsets. We will investigate the regulation of HIV infection in the thymus by IFN-gamma, since we have found that IFN-gamma inhibits HIV production by thymocytes in vitro. Low iFN-gamma levels at birth could be one factor in perinatal HIV transmission. The study of the effects of viral isolates with different cytopathogenicity on the maturation and function of immature T lymphocytes in the thymus provides an opportunity to define indicators of disease aggressiveness in pediatric patients and specific targets for medical intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029341-08
Application #
6182160
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Nugent, Robert
Project Start
1992-06-01
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2002-05-31
Support Year
8
Fiscal Year
2000
Total Cost
$263,238
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Krogstad, P; Uittenbogaart, C H; Dickover, R et al. (1999) Primary HIV infection of infants: the effects of somatic growth on lymphocyte and virus dynamics. Clin Immunol 92:25-33
Schmid, I; Ferbas, J; Uittenbogaart, C H et al. (1999) Flow cytometric analysis of live cell proliferation and phenotype in populations with low viability. Cytometry 35:64-74
Pedroza-Martins, L; Gurney, K B; Torbett, B E et al. (1998) Differential tropism and replication kinetics of human immunodeficiency virus type 1 isolates in thymocytes: coreceptor expression allows viral entry, but productive infection of distinct subsets is determined at the postentry level. J Virol 72:9441-52
Economides, A; Schmid, I; Anisman-Posner, D J et al. (1998) Apoptosis in cord blood T lymphocytes from infants of human immunodeficiency virus-infected mothers. Clin Diagn Lab Immunol 5:230-4

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