The objective of this study is to elucidate those early events in HIV infection that may lead to pathogenesis. Macrophages are infected in the circulatory system as well as in the brain. We have identified the early innate immunological responses following HIV infection of primary human macrophages: induction of the chemokines CXCL8 and CXCL10. CXCL8 recruits neutrophils, which are the hallmark of acute inflammation and can mediate tissue damage;CXCL10, also generated by the HIV-infected macrophage, recruits activated CD4 T cells and more macrophages, which become productively infected by the macrophage HIV particles. This year we have shown that these responses are immediate and define them as results of direct HIV-cell interactions, and as one of the earliest immunological responses to the virus. This year we also constructed continuous-culture cell lines that possess the innate immunological systems found in human primary macrophages and microglia. This will permit us to define the elements of the HIV virus, as well as those of the human cell, that are responsible for innate immunological activation by HIV. Nef is the first gene expressed in newly infected cells, and is central, through an undefined activity, to pathogenesis. This year we have placed Nef molecular activities at the level of cellular kinases regulating cell polarity and with adaptor proteins responsible for cell signaling and intracellular transport. Finding fundamental cellular activities for this viral protein is likely to help resolve its biochemical role in AIDS development, and understanding the molecular activities of this HIV protein opens potential points of intervention. Future efforts will include identifying the mechanism(s) of CXCL8 and CXCL10 induction by HIV infection of macrophages, and how this might contribute to pathogenesis. We will also continue our exploration of the biochemical activity of the Nef protein.
