title: Fungal metabolite myriocin promotes human herpes simplex virus-2 infection.
abstract: OBJECTIVE
  Myriocin is a fungal metabolite with antiviral activity, including influenza, hepatitis B, and hepatitis C viruses. We investigated whether myriocin has activity against human HSV-2, one of the most prevalent pathogens of sexually transmitted disease.
  
  
  METHODS
  Cell culture systems were used to evaluate myriocin effect on HSV-2 infection. Plaque forming assay and immunoblotting studies were used to determine virus production and viral protein expression, respectively.
  
  
  RESULTS
  Myriocin showed no cytotoxic effect at up to 5 μM. Myriocin treatment did not inhibit HSV-2 infection. Instead, the treatment resulted in accelerated replication of HSV-2 and increased titers of infectious virion. The effect was detected at concentrations as low as 3 nM and plateaued at approximately 30 nM. Myriocin at 30 nM increased HSV-2 production by approximately 1.7 logs. Myriocin also promoted HSV-1 infection but required higher concentrations. A time course study revealed that myriocin promoted HSV-2 infection by acceleration of virus replication. Unlike trichostatin A that promotes HSV-2 infection and histone modifications, myriocin treatment did not alter histone modifications. Myriocin is a well characterized inhibitor of sphingolipid biosynthesis pathway. Structurally different inhibitors of the pathway showed no effect on HSV-2 infection. Exogenous sphingolipids did not reverse the effect of myriocin on HSV-2 infection either.
  
  
  CONCLUSIONS
  We found that myriocin promotes HSV-2 replication at nanomolar concentrations with yet unknown mechanisms. Further studies may uncover novel mechanisms regulating HSV replication and targets of myriocin action. This may have potential application in enhancing efficacy of oncolytic HSV for cancer therapy and other diseases.
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Xuancheng
authors.initials: X
authors.lastname: Guo
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Ren-Xiang
authors.initials: RX
authors.lastname: Tan
authors.affiliation: Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, China. Electronic address: ahuchxq@126.com.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China. Electronic address: erguang@nju.edu.cn.
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D006561:Herpes Simplex / Q000188:drug therapy*; D018258:Herpesvirus 2, Human / Q000378:metabolism* / Q000502:physiology*; D006657:Histones / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D013107:Sphingolipids / Q000737:chemistry; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D005229:Fatty Acids, Monounsaturated; D006657:Histones; D006877:Hydroxamic Acids; D013107:Sphingolipids; C012589:trichostatin A; C001996:thermozymocidin
keywords: HSV-2; Herpes simplex virus; Histone modification; Myriocin; Sphingolipid