HIV-associated dementia is an important complication of viral infection and a cause of significant morbidity and mortality. The cardinal feature of HIV-1 induced neurological disease is productive viral replication in monocyte-derived macrophages (MP). Macaques infected with SIV/SHIV viruses have provided excellent working models for recapitulating the HIV-CNS disease. Although lentiviral-encephalitis (LV-E) is primarily associated with CCR5-utilizing viruses, our findings have shown that CXCR4 (X4)-utilizing SHIVs were also capable of causing the syndrome in rhesus macaques. In SHIV (X4)-infected animals, typical LV-E was almost always accompanied by concurrent opportunistic infections in the brain. Inevitably these secondary infections were accompanied by strong Th2immune responses as evident by presence of interleukin (IL)-4 in encephalitic brains. We have already established thatIL-4 enhanced both, viral replication and expression of macrophage chemoattractant protein (MCP)-I in MP cultures and that, addition of antisense IL-4 DNA curtailed viral replication in these cells. Our recent microarray analyses have confirmed up-regulation of IL-4, MCP-1, platelet-derived growth factor (PDGF)-B chain, a known inducer of MCP-1and interferon-inducible peptide, IP-10, in the brains of macaque with SHIV-encephalitis. Based on these findings, we hypothesize that: 1) PDGF, a factor that has never thus far been implicated in LV-E plays a vital role in promoting virus replication in MP, either through induction of MCP-1 or through an independent pathway, and 2) IP-10 over-expression in the brains of macaques with LV-E contributes to the end-stage neuronal dysfunction. In this application we will test the hypothesis in 4 specific Aims: 1) To define the role of PDGF in virus replication in macaque MP cultures. 2) To assess the role of IP-10 and its receptor, CXCR3 in neuronal dysfunction/death. 3) Optimize liposome:DNA complexes(LDC) containing antisense DNAs of IL-4, PDGF-B chain & MCP-1 for delivery in macaque MP cultures infected withSH1V89.6P. 4) Optimization of LDC containing antisense IL-4, PDGF-B & MCP-1 DNAs for in vivo gene delivery in small animals, such as mice before aiming gene therapy in infected macaques.
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