HIV encephalitis is a common and devastating sequela to HIV-1 infection in human beings. A nearly identical syndrome exists in rhesus monkeys infected with simian immunodeficiency virus (SIV). Not all human patients infected with HIV-1 or rhesus monkeys infected with SIV develop AIDS encephalitis, therefore, unknown viral or host factors acting alone, or in concert, must be important for the development of AIDS encephalitis. The recruitment of lentivirus-infected leukocytes to the brain early in infection may be a crucial factor in initiating and potentiating this process. It is well established that leukocyte recruitment to sites of inflammation is mediated by increased expression and avidity of adhesion molecules on both endothelium and leukocytes. Therefore, using the SIV- infected macaque model of AIDS, we propose to examine the role of leukocyte and endothelial interactions in the pathogenesis of HIV encephalitis. Our hypothesis is that selective recruitment and retention of mononuclear cells to the brain is critical for the induction of AIDS encephalitis. Furthermore, we believe that perturbations of adhesion between circulating leukocytes and the brain endothelium occur secondary to selective adhesion molecule and/or chemokine expression. To test our hypotheses we plan to: 1) Examine the role of viral determinants on the sequential recruitment of leukocytes to the brain early in infection and determine what role early cell trafficking has on the development of SIV encephalitis by evaluating the differences in recruitment of fluorescently-labeled leukocytes to the brain in rhesus monkeys infected with SIVmac239 which replicates poorly in macrophages, SIVmac239/3 16 Em, a macrophage competent molecularly cloned variant of SIVmac239, and the nonpathogenic molecular clone SIVmac239/nef- deletion. 2) Determine the host factors involved in selective leukocyte recruitment to brain by examining the sequential expression of leukocyte and endothelial-derived adhesion molecules, cytokines, and chemokines in the brain and correlating their association with the onset of cellular infiltrates. 3) Block relevant adhesion molecule function in vivo to determine the specificity of endothelial and/or leukocyte adhesion molecules in leukocyte trafficking to the brain early in SIV infection. 4) Examine the ability of proinflammatory agents to induce adhesion molecule expression on brain endothelium in vitro and in vivo. We believe that a time-course study using the SIV macaque model is the best approach to investigating both viral and host parameters involved in leukocyte recruitment to the brain in AIDS encephalitis.
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