HIV-1 infection and AIDS remain a major worldwide public health problem, and efforts toward understanding how the virus causes immunodeficiency and toward developing novel therapies are still required, despite the advent of highly active antiretroviral therapy (HAART). Increased homing of T cells to lymphoid tissues (LTs) during HIV-1 infection, with loss through direct infection/killing or bystander killing, has been proposed as one mechanism contributing to the development of immunodeficiency. In addition, increased homing of CD4+ T cells and its amelioration following HAART have been demonstrated in HIV-1- infected patients. The causes and consequences of altered homing of leukocytes to LTs are not fully understood and these issues constitute a major focus of this proposal. A comprehensive understanding of the mechanisms that lead to changes in homing to LTs will identify possible targets for immunotherapy. Our overall hypothesis for these studies is that alterations in chemokine expression in LTs contribute to the development of immunodeficiency during HIV-1 infection. Using the SIV/macaque model system, we have made initial observations regarding the alteration of chemokine expression in lymph nodes (LNs) and spleen, but comprehensive analyses are required to fully understand the magnitude of alterations and their causes and consequences. Based on our initial findings we have proposed a model for type 1, IFN-y-driven positive feedback loops that sustain the ongoing recruitment of type 1 T cells into LTs. However, this model has not been addressed experimentally and we propose to do exactly this by therapeutically modulating the recruitment of cells into LTs during SIV infection.
The Specific Aims of this proposal are to: (1) Define alterations in the networks of chemokines in macaque LTs during pathogenic SIV infection; (2) Determine the biochemical properties of inflammatory and homeostatic macaque chemokines that could be involved in HIV/SIV immunopathogenesis; and (3) Determine the virologic and immunologic effects of systemic treatment of SIV infected macaques with chemokine receptor antagonists.
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