HIV-1 infection can lead to impaired antigen-specific T cell proliferation and Th1 responses, increased T cell apoptosis, and altered maturation or maintenance of memory cells. We have identified similar abnormalities in HIV-1 Tg rats, including increased susceptibility of T cells to activation-induced apoptosis, a reduced ability to produce IFN-gamma and IL-2 following activation, and an increased ratio of sizes of effector/memory-phenotype (CD45RC-CD62L() to naive (CD45RC+CD62L+) T cell pools that develops with time. Our central hypothesis is that these T cell defects occur through a block in memory lineage development, defective homeostatic proliferation of effector/memory-phenotype T cells, and/or increased activation-induced apoptosis of effector/memory cells.
Three Specific Aims address this central hypothesis.
Aim 1 will characterize functional defects in naturally occurring central memory (CD45RC(CD62L+) and/or effector/memory-phenotype T cells.
Aim 2 will compare in vitro proliferation and the induction of apoptosis relative to cell division of central memory-phenotype and effector/memory-phenotype T cells following anti-CD3 and -CD28 stimulation. We will compare the ability of naive and effector/memory-phenotype T cell populations to persist by homeostatic mechanisms following adoptive transfer into Tg rats and age-matched controls. We will determine if early death is occurring in effector/memory-phenotype T cells and is accompanied a by compensatory increase in the na?ve phenotype pool by measuring population kinetics of naive and memory/effector-phenotype T cell subsets.
Aim 3 will identify the critical HIV-1 gene product(s) by developing Tg rats that express specific HIV genes. Our goals are to understand how expression of HIV gene products causes defects in the development or maintenance of T cell effector function in Tg rats and to identify the relevant viral gene.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI063171-05
Application #
7575509
Study Section
Special Emphasis Panel (ZAI1-GPJ-M (M1))
Program Officer
Finzi, Diana
Project Start
2004-09-01
Project End
2008-02-29
Budget Start
2007-07-01
Budget End
2008-02-29
Support Year
5
Fiscal Year
2007
Total Cost
$284,454
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201