title: Interleukin-1 and tumor necrosis factor-α trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID).
abstract: Virus infection is restricted by intracellular immune responses in host cells, and this is typically modulated by stimulation of cytokines. The cytokines and host factors that determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1β and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A cytidine deaminase, activation-induced cytidine deaminase (AID), was up-regulated by both IL-1β and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knockdown of AID expression impaired the anti-HBV effect of IL-1β, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection.
authors.affiliation: From the Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.forename: Guoxin
authors.initials: G
authors.lastname: Liang
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
authors.forename: Nanako
authors.initials: N
authors.lastname: Uchida
authors.forename: Takuji
authors.initials: T
authors.lastname: Daito
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kitamura
authors.forename: Masamichi
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kiyohara
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Suzuki
authors.forename: Jisu
authors.initials: J
authors.lastname: Li
authors.forename: Shuping
authors.initials: S
authors.lastname: Tong
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Murata
authors.forename: Hideki
authors.initials: H
authors.lastname: Aizaki
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
mesh_terms: D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006509:Hepatitis B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004279:DNA, Viral; C508585:IL1B protein, human; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: AID; APOBEC3G; Deaminase; HBV; HepaRG; Innate Immunity; Interferon; Interleukin; Tumor Necrosis Factor (TNF); Virus
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