Cytotoxic T lymphocytes (CTL) play a critical role in host defense against viral infections, including HIV-1. Chemokines play an important role in several aspects of CTL function as CTL both produce and respond to chemokines. Chemokine receptors on CD8+ T lymphocyte have recently been implicated in their cytolytic function and survival. In addition, it is becoming increasing clear that chemokines play a critical role in regulating T cell trafficking and it is likely that chemokines also control the trafficking of CTL. In order to effectively control viral replication CTL need to be recruited into tissue compartments where there is active replication and this is an important consideration for vaccine development. Little is known about what controls CTL trafficking in vivo and it is likely that chemokines and their receptors play an important role in this process. In preliminary studies, we have seen that the CXCR3 chemokine receptor is highly upregulated on HIV-1-specific CTL activated in vitro and is highly expressed on CTL found in tissue compartments of patients with ongoing HIV replication. In addition, CXCR3 was found on HLA-A2 Gag tetramer positive CD8+ lymphocytes found in peripheral blood of a non-progressor but not on peripheral blood CTL of patients with progressive disease. Our central hypothesis is that chemokines control the trafficking and regulate the function of CTL in HIV disease and, in particular, CXCR3 and its ligand, IP-10, play an important role in recruiting CTL into HIV-1 infected tissue. Specifically we propose: 1) To determine the expression and function chemokine receptors on tetramer positive activated bulk CD8+ T cells and CTL clones. Functional analysis will include chemotaxis, calcium flux, target cell lysis, inhibition of p24 production, and cytokine release. The role of chemokines and their receptors in regulating CTL apoptosis will also be determined; 2) To determine the expression of chemokine receptors on CTL in the blood and tissues of patients with HIV-1 infection with varied disease progressions. In addition, to more comprehensively study the kinetics of chemokine receptor expression over time in vivo, we will use the SIV macaque model of AIDS to study tetramer positive CD8+ lymphocytes in the blood and tissue compartments in SIV-1 infected macaques over time; and 3) To determine the role of IP-10 in CTL trafficking in vivo in the murine models of Toxoplasma gondii and LCMV infection using genetically modified mice deficient in IP-10 and neutralizing mAbs to murine IP-10.
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