HIV-associated dementia (HAD) is an important complication of viral infection and a cause of significant morbidity and mortality. Although the primary cell types infected by HIV-1 in the brain are macrophages/microglia, and to a lesser extent, astrocytes but NOT neurons, the low numbers of infected cells in the brain do not correlate with the extent of neuropathogenesis observed in HIV encephalitis (HIV-E). Instead, activation of glia through direct infection or their interactions with infected cells, their products, or viral particles, contribute to the severe neuropathological abnormalities associated with HAD. It is becoming increasingly evident that the interplay of factors (cytokines, chemokines and/or viral proteins) released from activated astroglial cells play a crucial role in orchestrating the amplification of toxic inflammatory cascades that ultimately lead to progressive loss of neuronal function. While the previous period of funding was focused on identifying soluble mediators that were involved in the pathogenesis of X4 SHIV/Rhesus macaque model of NeuroAIDS, the renewal will focus on viral & cellular interactive loops in the generation of the neurotoxin, CXCL10, in the context of R5 viruses, with relevance to human CNS disease. Two aspects will be considered for these studies: a) synergistic effect of HIV-1/viral proteins in the induction of IFN-3 inducible neurotoxin, CXCL10 and b) PDGF-mediated neuroprotection against combined toxicity of viral proteins/cytokines & CXCL10. Such a combinatorial approach is consistent with the long-term translational goal of developing novel experimental therapeutics for HAD that will be aimed at mitigating CXCL10 toxicity and concomitant neuronal degeneration in the CNS. Proposed hypotheses will be tested in three specific aims: 1) To examine the synergistic effects of HIV-1 proteins, and pro-inflammatory cytokines on CXCL10 gene expression by astrocytes; 2) To investigate the role of PDGF in protection against viral protein/cytokine/CXCL10-mediated neuronal apoptosis & 3) In vivo delivery of antisense CXCL10 & PDGF DNA as therapy for abrogating HIV-neurotoxicity in murine models of HIV-1 CNS disease.
This proposal aims to: a) Explore the interplay of vial and/or host factors in mediating astrocyte activation & neuronal dysfunction and, b) Develop therapeutic intervention strategies aimed at reducing HIV neurotoxicity. ? ? ?
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