Role of Monocytes in AIDS and as Targets for Antiviral Therapy

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Research in this project is directed at understanding the mechanisms of HIV-1 infection, particularly in macrophages, and in developing an effective strategy to prevent and/or inhibit infection. Immunodeficiency, the consequence of HIV-1 infection, predisposes the host to opportunistic infections. In turn, opportunistic infections influence target cell susceptibility to HIV-1 infection and replication. Using M. avium as a model co-pathogen, we have defined multiple viral permissive factors. Moreover, immune activation as occurs in tonsils and non-infectious mucosal inflammatory lesions may also be associated with proximal sites of viral replication. These connections between activation/inflammation and enhancement of HIV-1 infection warrant further elucidation of the factors promoting permissiveness to HIV-1. The tonsil represents an unique microenvironment possessing a large reservoir of activated and highly susceptible HIV targets. By isolating and culturing tonsil cells with HIV, phenotypic, functional and molecular correlates of enhanced susceptibility, as compared to less sensitive peripheral blood mononuclear cells, can be established and provide insight into interventional targets. The mucosal surface is also a site of maternal-to-child HIV transmission during breastfeeding and efforts are directed at defining the kinetics of transmission and the expression of innate and acquired host defense mechanisms which impact on viral transmission. Endogenous antiviral molecules, including secretory leukocyte protease inhibitor (SLPI) and thrombospondin (TSP-1), which have inhibitory actions on HIV-1 infection of mononuclear cells, are found in colostrum and then decline suggesting a potential interval of enhanced defense.