Gp120, Macrophage Activation & TNF in HIV Encephalopathy

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HIV-associated dementia (HAD) is initiated by HIV-1 replication within the brain, and activation of both uninfected & infected brain macrophage/microglia (M/M) is a critical element that is closely linked to clinical disease. Extensive research has implicated products of HIV-stimulated M/M in pathogenesis, such as TNF-a, which is elevated in HAD, produced by activated M/M in the brain, and appears to play an important role in neuronal injury & the perpetuation of activation. Although much is known about potential mediators & neurotoxins that are released by activated M/M in HAD, it remains unknown how HIV-1 triggers M/M activation to initiate the events that culminate in neuronal injury and this is an important gap in our understanding of HAD pathogenesis. To enter cells, HIV binds CD4 followed by one of two chemokine receptors, CCR5 or CXCR4. Chemokine receptors' normal function is to mediate activation & chemotaxis in response to extracellular stimuli. CD4's function and signaling are well-defined in T cells, but little is known about CD4 function or signaling in macrophages. In preliminary studies, we found that HIV-1 Env glycoprotein gp120 binding to both CD4 & chemokine receptors on M/M initiates intracellular signaling, and that activation of specific pathways through these receptors leads to cellular activation and release of inflammatory mediators including TNF-a & other products implicated in HAD pathogenesis. Our hypothesis is that M/M activation in the brain results, in part, from gp120 interaction with CD4 & chemokine receptors, eliciting intracellular signals that lead to production of inflammatory & neurotoxic mediators such as TNF-a, which initiates a cascade of inflammation, activation &, ultimately, neuronal injury. Our goal is to define specific molecular mechanisms by which HIV-1 gp120 triggers M/M activation in the brain relevant to HAD pathogenesis. To do this we will: (1) Identify mechanism & pathways by which HIV-1 gp120 regulates TNF-a production in M/M: (2) Define the pathways for CD4-mediated signaling in primary macrophages: (3) Determine the effect on macrophage TNF-a induction of viral & host genetic factors linked to HAD, and; (4) Define & compare the patterns of altered macrophage gene expression in vitro elicited by gp120 & in vivo in HAD. We anticipate that these studies will provide insight into initiating mechanisms of cellular activation in HAD, as well as, ultimately, provide a rational basis for targeted strategies to interfere with this process.