RT Journal Article
SR Electronic
T1 Stimulation of the liver X receptor pathway inhibits HIV-1 replication via induction of ATP binding cassette transporter A1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.065029
DO 10.1124/mol.110.065029
A1 Matthew P Morrow
A1 Angela Grant
A1 Zahedi Mujawar
A1 Larisa Dubrovsky
A1 Tatiana Pushkarsky
A1 Yana Kiselyeva
A1 Lucas Jennelle
A1 Nigora Mukhamedova
A1 Alan T Remaley
A1 Fatah Kashanchi
A1 Dmitri Sviridov
A1 Michael Bukrinsky
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/05/17/mol.110.065029.abstract
AB Cholesterol plays an important role in HIV life cycle, and infectivity of cholesterol-depleted HIV virions is significantly impaired. Recently, we demonstrated that HIV-1, via its protein Nef, inhibits activity of the major cellular cholesterol transporter, ATP binding cassette transporter A1 (ABCA1), suggesting that the virus may use this mechanism to get access to cellular cholesterol. In this study, we investigated the effect on HIV infection of a synthetic liver X receptor (LXR) ligand, TO-901317, which is a potent stimulator of ABCA1 expression. We demonstrate that TO-901317 restores cholesterol efflux from HIV infected T lymphocytes and macrophages. TO-901317 potently suppressed HIV-1 replication in both cell types, 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, and RNAi-mediated inhibition of ABCA1 expression eliminated the effect of TO-901317 on HIV-1 replication. TO-901317-mediated inhibition of HIV replication was due to reduced virus production and reduced infectivity of produced virions. The infectivity defect was due in part to reduced fusion activity of the virions, which was directly linked to reduced viral cholesterol. These results describe a novel approach to inhibit HIV infection by stimulating ABCA1 expression.The American Society for Pharmacology and Experimental Therapeutics