HIV-1 associated dementia is an important complication of viral infection and a cause of significant morbidity and mortality. The underlying feature of HIV-1 induced neurological disease is immune activation and viral replication in monocyte-derived macrophages (MP) and microglial (MG) cells. These cells are the major, if not exclusive, cellular targets for productive viral infection in the brain. Macaques infected with SIV/SHIV viruses, have provided excellent working models for recapitulating the HIV-CNS disease. These macaques infected with pathogenic SIVmac251, SHIV89.6 and SHIVKU-2 rapidly succumb to AIDS. However, lentiviral encephalitis associated with viral infection in MP and MG was only observed in macaques infected with CCR5-utilizing viruses, SIVMAC251 and SHIV89.6P. In contrast, SHIVKU-2, a CXCR4-utilizing virus which is able to infect MP in culture, failed to cause CNS disease in these animals. In the CNS, infection of the MG by HIV-1 mainly occurs throughout the usage of CCR5 and CCR3 co-receptors; infection with CXCR4-utilizing HIV-1 being relatively inefficient. In addition to viral tropism, cytokine-chemokine interactions play a replication and expression of macrophage chemoattractant protein (MCP)-1 in macrophage cultures and that addition of antisense IL-4 DNA curtails viral replication in these cells. Based on these findings we hypothesize that: 1) the neurovirulent potential of CCR5-utilizing viruses depends on their ability to replicate productively in both, macaque MG and MP and that IL-4 will enhance both, viral replication, and expression of MCP-1 in these cells. The lack of SHIVKU-2 to induce lentiviral CNS disease could thus be related to its inability to use CCR5 co-receptor. 2) Treatment of infected MP with antisense DNA of IL-4 will cause curtailment of viral replication. In this application we will test the hy0otheses in three specific AIMS: 1 (To assess the modulation of viral replication and CMP-1 expression in macaque MP and MG cultures inoculated with SIVMAC251, SHIV89.6P and SHIVKU-2 in the presence of IL-4 and antisense IL-4 oligodeoxynucleotide. 2) Optimize liposome: DNS complex (LDC) containing antisense IL-4 DNA to macaque MP cultures infected with SHIV89.6P. 3) Optimization of LDC containing antisense IL-4 DNA for in vivo gene delivery in small animals, such as mice before aiming gene therapy in infected macaques (not a part of this proposal).
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