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.
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| Yadav, Anjana; Fitzgerald, Phillip; Sajadi, Mohammad M et al. (2009) Increased expression of suppressor of cytokine signaling-1 (SOCS-1): A mechanism for dysregulated T helper-1 responses in HIV-1 disease. Virology 385:126-33 |
| Yadav, Anjana; Pati, Shibani; Nyugen, Anhthu et al. (2006) HIV-1 transgenic rat CD4+ T cells develop decreased CD28 responsiveness and suboptimal Lck tyrosine dephosphorylation following activation. Virology 353:357-65 |
