title: Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection.
abstract: Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV. Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks postinfection substantially reduced viral load. When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock-treated controls. T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice. In conclusion, these results reveal a novel link between LXR stimulation and cell resistance to HIV infection and suggest that LXR agonists may be good candidates for development as anti-HIV agents, in particular for pre-exposure prophylaxis of HIV infection.
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Ali
authors.initials: A
authors.lastname: Ramezani
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Larisa
authors.initials: L
authors.lastname: Dubrovsky
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pushkarsky
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Sara
authors.initials: S
authors.lastname: Karandish
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Raj
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.).
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.affiliation: George Washington University School of Medicine and Health Sciences, Washington, DC (A.R., L.D., T.P., S.K., D.S.R., M.B.); Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia (D.S.); and Harvard Medical School, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts (M.L.F.) mbukrins@gwu.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Bukrinsky
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000821:virology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D019562:Viral Load / Q000379:methods; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D019380:Anti-HIV Agents; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides