The Role of ABCA1 in HIV-1 Infectivity Open Access
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ABCA1 is an integral transmembrane protein that facilitates the transport of intracellular cholesterol and phospholipids to the extracellular acceptor ApoA-I, the process termed cholesterol efflux. HIV-1 infection impairs ABCA1-mediated cholesterol efflux and down regulates ABCA1 protein expression. Mechanistically, this impairment is mediated by the viral protein Nef. During infection, Nef increases viral infectivity by increasing the cholesterol content of the virions produced from infected cells through increasing the cholesterol content of lipid rafts. Due to the importance of cholesterol in the HIV-1 lifecycle, we sought to determine the role of ABCA1 in HIV-1 infectivity. In this study, we demonstrate that Nef mediates cholesterol delivery to lipid rafts through the inhibition of ABCA1-mediated cholesterol efflux and downregulation of ABCA1 protein expression via lysosomal degradation. We go on to demonstrate that pharmacological stimulation of ABCA1 expression using the LXR agonist TO-901317 reverses the HIV-induced inhibition of ABCA1-mediated cholesterol efflux and ABCA1 protein expression in infected cells. TO-901317 potently suppressed HIV-1 replication in vitro, and also inhibited HIV-1 replication in ex vivo cultured lymphoid tissue and in RAG-hu mice infected in vivo. This anti-HIV activity was dependent on ABCA1, as the effect of the drug was significantly reduced in ABCA1-defective T cells from a Tangier disease patient. TO-901317-mediated inhibition of HIV replication was due to both reduced virus production and reduced infectivity of produced virions. The infectivity defect was due in part to the inhibition of Nef-mediated cholesterol delivery to lipid rafts, which caused the reduced viral cholesterol content. These results describe a novel approach to inhibit HIV infection by stimulating ABCA1 expression.