ANTI HIV MOLECULAR THERAPEUTICS TARGETING CHEMOKINE RECEPTORS

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Human immunodeficiency virus type I (HIV-1)-induced encephalopathy is an enigmatic syndrome which occurs in a sizable group of patients with AIDS, characterized by cognitive, motor and sensory deficits. The underlying neuropathogenesis of this syndrome remains unclear. Recently, it has been demonstrated that alpha- and beta-chemokine receptors are the major co-receptors for HIV-1, and determine cell- specific viral strain tropism. Initial studies have now demonstrated that chemokine and chemokine receptors are expressed on central nervous system, (CNS)-based cells. As well, alterations in chemokine and chemokine receptor expression in the CNS during HIV-1 infection have also now been reported. As such, chemokine and chemokine receptors may b directly involved with HIV-1induced encephalopathy. We propose to inhibit chemokine receptors in specific CNS-based cells utilizing intracellular immunization approaches and single chain variable fragments (SFvs). Initial studies will develop anti-chemokine receptor SFvs, both human and murine. The CXCR-4, CCR3 chemokine receptors will be the relevant initial molecular targets. After development of human and murine SFVS to the relevant chemokine receptors, these constructs will be tested for their ability to inhibit HIV-1 replication in primary human CNS cell-types. In addition, the effects of altering chemokine interactions with CNS-based cells during HIV-1 infection will be characterized. Both murine leukemia virus vectors and newly designed lentiviral vectors, which transduce non-proliferating cell-types, will be utilized. The molecular mechanisms effects on CNS-based cells (e.g., apoptosis) will be analyzed, based on chemokine receptor intracellular inhibition. These studies will directly interact with several projects within this program and promise to both assist in understanding the neuropathogenesis of HIV-1 infection and move towards our long-term goal of designing relevant and complementary CNS therapeutics in patients with HIV-1 infection.