title: Beta interferon plus gamma interferon efficiently reduces acyclovir-resistant herpes simplex virus infection in mice in a T-cell-independent manner.
abstract: Acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) causes severe diseases in immunocompromised patients, so identification of new therapies is needed. Interferons (IFNs) are used to treat several other viral infections in the clinic, and IFN-beta and IFN-gamma are known to cooperatively reduce wild-type HSV-1 replication in the corneas of immunocompetent mice. Because IFN-gamma has been shown to exert an antiviral effect mostly through T cells, whether combined IFN treatment can still inhibit ACV-resistant HSV-1 replication, especially in immunocompromised hosts, is unknown. The present study evaluated the efficacy of combined IFN treatment on ACV-resistant HSV-1 mutants. In vitro results showed that IFN-beta acted synergistically with IFN-gamma to inhibit HSV-1 replication in both human and mouse cell lines. Some ACV-resistant mutants were actually hypersensitive to combined IFN treatment. In vivo results showed that topical treatment with a low dose of IFN-beta plus IFN-gamma (200 U each) on mouse corneas efficiently reduced the viral loads by up to 4, 4 and 3 logs, respectively, in the eyes, trigeminal ganglia and brainstems of wild-type and also immunocompromised nude mice infected or co-infected with ACV-resistant HSV-1 in a manner independent of T cells. A highly efficient reduction in HSV acute replication by combined IFN treatment led to a dramatic decrease in subsequent virus reactivation from neural tissues, trigeminal ganglia, brainstems and spinal cords of latently infected mice. Thus, a combination of IFN-beta and IFN-gamma could be a potential treatment for ACV-resistant HSV-1 in immunocompromised patients.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan 70101, PR China.
authors.forename: Wen-Yen
authors.initials: WY
authors.lastname: Huang
authors.forename: Ying-Hsiu
authors.initials: YH
authors.lastname: Su
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yao
authors.forename: Ping
authors.initials: P
authors.lastname: Ling
authors.forename: Yuk-Ying
authors.initials: YY
authors.lastname: Tung
authors.forename: Shih-Heng
authors.initials: SH
authors.lastname: Chen
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Wang
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
mesh_terms: D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001933:Brain Stem / Q000821:virology; D002460:Cell Line; D003315:Cornea / Q000821:virology; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D012668:Trigeminal Ganglion / Q000821:virology; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016899:Interferon-beta; D007371:Interferon-gamma; D000212:Acyclovir