eCD4-mediated control of SIV infection in the brain

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PROJECT SUMMARY Combined antiretroviral therapy (ART) has revolutionized the treatment of HIV but ART regimens are not without drawbacks. Cost, the need for daily administration, side effects, and social stigma all contribute to reduced patient compliance. Moreover, despite treatment, some 15-55% of people living with HIV will develop some form of HIV-associated neurocognitive disorder (HAND). Because of these problems with ART regimens, we and many other investigators have been studying the use of recombinant adeno-associated virus (rAAV) gene therapy vectors to deliver antibodies and other HIV therapeutics to people living with HIV. Because expression from these vectors is essentially permanent; patients could be protected for life from HIV infections with only a single AAV treatment (i.e. a ‘functional’ cure). Although numerous nonhuman primate experiments and two human clinical trials have been conducted to study the use of AAV for functional cure, however, we are unaware of any efforts to determine whether or not rAAV-expressed biologics can prevent or treat HAND. We have developed an anti-HIV biologic called eCD4, a fusion of CD4-Ig with a carboxy-terminal co-receptor (CCR5/CXCR4) mimetic peptide. We hypothesize that eCD4 is uniquely suited to preventing replication of the neurotropic strains of HIV that preferentially infect the brain (macrophage-tropic isolates) because these viruses necessarily evolve high affinity for CD4 to compensate for the low abundance of CD4 on macrophages and microglia. The organizing hypothesis of this project, then, is to determine if rAAV-delivered eCD4, either expressed from the periphery or within the central nervous system, can prevent or treat HAND. To test this hypothesis, we will use a pigtail macaque model of SIV-induced central nervous system disease, developed in our laboratories, in which co-infection with an immunosuppressive swarm (SIV/DeltaB670) and neurotropic clone (SIV/17E-Fr) establishes a highly reproducible CNS infection. Animals will be treated with ART until aviremic and rAAV will be used to deliver a pigtail macaque version of eCD4 to skeletal muscle and/or brain tissue. ART will be withdrawn to determine whether or not rAAV/eCD4 can prevent the re-emergence of CNS viremia. If successful, these studies may open new avenues to the functional cure of HIV and treatment of HAND.