title: HIV integrase inhibitors block replication of alpha-, beta-, and gammaherpesviruses.
abstract: The catalytic site of the HIV integrase is contained within an RNase H-like fold, and numerous drugs have been developed that bind to this site and inhibit its activity. Herpes simplex virus (HSV) encodes two proteins with potential RNase H-like folds, the infected cell protein 8 (ICP8) DNA-binding protein, which is necessary for viral DNA replication and exhibits recombinase activity in vitro, and the viral terminase, which is essential for viral DNA cleavage and packaging. Therefore, we hypothesized that HIV integrase inhibitors might also inhibit HSV replication by targeting ICP8 and/or the terminase. To test this, we evaluated the effect of 118-D-24, a potent HIV integrase inhibitor, on HSV replication. We found that 118-D-24 inhibited HSV-1 replication in cell culture at submillimolar concentrations. To identify more potent inhibitors of HSV replication, we screened a panel of integrase inhibitors, and one compound with greater anti-HSV-1 activity, XZ45, was chosen for further analysis. XZ45 significantly inhibited HSV-1 and HSV-2 replication in different cell types, with 50% inhibitory concentrations that were approximately 1 µM, but exhibited low cytotoxicity, with a 50% cytotoxic concentration greater than 500 µM. XZ45 blocked HSV viral DNA replication and late gene expression. XZ45 also inhibited viral recombination in infected cells and ICP8 recombinase activity in vitro. Furthermore, XZ45 inhibited human cytomegalovirus replication and induction of Kaposi's sarcoma herpesvirus from latent infection. Our results argue that inhibitors of enzymes with RNase H-like folds may represent a general antiviral strategy, which is useful not only against HIV but also against herpesviruses. Importance: The herpesviruses cause considerable morbidity and mortality. Nucleoside analogs have served as effective antiviral agents against the herpesviruses, but resistance can arise through viral mutation. Second-line anti-herpes drugs have limitations in terms of pharmacokinetic properties and/or toxicity, so there is a great need for additional drugs for treatment of herpesviral infections. This study showed that the HIV integrase inhibitors also block herpesviral infection, raising the important potential of a new class of anti-herpes drugs and the prospect of drugs that combat both HIV and the herpesviruses.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Bryant
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Gregory
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Angelova
authors.affiliation: Allergy and Clinical Immunology/Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Dreyfus
authors.affiliation: Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland, USA.
authors.forename: Xue Zhi
authors.initials: XZ
authors.lastname: Zhao
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Coen
authors.affiliation: Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland, USA.
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA david_knipe@hms.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000187:drug effects; D006801:Humans; D018139:Simplexvirus / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019428:HIV Integrase Inhibitors