title: Sulfonation pathway inhibitors block reactivation of latent HIV-1.
abstract: Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful.
authors.affiliation: Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Murry
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Godoy
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Amey
authors.initials: A
authors.lastname: Mukim
authors.affiliation: Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Swann
authors.affiliation: Morgridge Institute for Research, Madison, WI, USA; Institute for Molecular Virology, University of Wisconsin, Madison, WI, USA; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Bruce
authors.affiliation: Morgridge Institute for Research, Madison, WI, USA; Institute for Molecular Virology, University of Wisconsin, Madison, WI, USA; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ahlquist
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA; Department of Pathology, University of California, San Diego, La Jolla, CA, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Celsa A
authors.initials: CA
authors.lastname: Spina
authors.affiliation: Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. Electronic address: jyoung@salk.edu.
authors.forename: John A T
authors.initials: JA
authors.lastname: Young
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D002704:Chlorates / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006139:Guaiacol / Q000008:administration & dosage / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D013451:Sulfonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000502:physiology
chemical_list: D019380:Anti-HIV Agents; D002704:Chlorates; D016328:NF-kappa B; D013451:Sulfonic Acids; D014409:Tumor Necrosis Factor-alpha; D006139:Guaiacol; D012319:RNA Polymerase II
keywords: Gene expression; HIV-1; Inhibitor; Latency; Primary CD4+ T cells; Reactivation; Sulfonation