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Interleukin-1 and tumor necrosis factor-α trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID).

Watashi K, Liang G, Iwamoto M, Marusawa H, Uchida N, Daito T, Kitamura K, Muramatsu M, Ohashi H, Kiyohara T, Suzuki R, Li J, Tong S, Tanaka Y, Murata K, Aizaki H, Wakita T - J. Biol. Chem. (2013)

Bottom Line: This effect was mediated by activation of the NF-κB signaling pathway.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.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.

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.

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Antiviral activity of AID was specific to HBV.A, Huh-7.5.1 cells were pretreated with IL-1β, TNFα, or IFNα for 3 h or left untreated and then coincubated with HCV for 4 h. After washing HCV and cytokines and culturing the cells with normal medium for 72 h, the infectivity of HCV (left panel) as well as HCV core protein (right panel) in the medium was quantified. B, HepaRG cells were treated with IL-1β or heparin or left untreated for 3 h prior to and 16 h during infection of HBV genotype A (left graph) or C (right graph) as shown in Fig. 1A. HBV infection was monitored with cellular HBV DNA at 12 days after the infection as Fig. 1C.
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Figure 7: Antiviral activity of AID was specific to HBV.A, Huh-7.5.1 cells were pretreated with IL-1β, TNFα, or IFNα for 3 h or left untreated and then coincubated with HCV for 4 h. After washing HCV and cytokines and culturing the cells with normal medium for 72 h, the infectivity of HCV (left panel) as well as HCV core protein (right panel) in the medium was quantified. B, HepaRG cells were treated with IL-1β or heparin or left untreated for 3 h prior to and 16 h during infection of HBV genotype A (left graph) or C (right graph) as shown in Fig. 1A. HBV infection was monitored with cellular HBV DNA at 12 days after the infection as Fig. 1C.

Mentions: HBV used in this study was mainly derived from HepAD38 cells, which is classified as genotype D (38). Media from HepAD38 cells at days 7–31 post-induction of HBV by depletion of tetracycline were recovered every 3 days. Media were cleared through a 0.45-μm filter and precipitated with 10% PEG8000 and 2.3% NaCl. The precipitates were washed and resuspended with medium at ∼200-fold concentration. The HBV DNA was quantified by real time PCR. HBV genotype A and C in Fig. 7B was recovered from the media of HepG2 cells transfected with the plasmid pHBV/Aeus and pHBV/C-AT (41).


Interleukin-1 and tumor necrosis factor-α trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID).

Watashi K, Liang G, Iwamoto M, Marusawa H, Uchida N, Daito T, Kitamura K, Muramatsu M, Ohashi H, Kiyohara T, Suzuki R, Li J, Tong S, Tanaka Y, Murata K, Aizaki H, Wakita T - J. Biol. Chem. (2013)

Antiviral activity of AID was specific to HBV.A, Huh-7.5.1 cells were pretreated with IL-1β, TNFα, or IFNα for 3 h or left untreated and then coincubated with HCV for 4 h. After washing HCV and cytokines and culturing the cells with normal medium for 72 h, the infectivity of HCV (left panel) as well as HCV core protein (right panel) in the medium was quantified. B, HepaRG cells were treated with IL-1β or heparin or left untreated for 3 h prior to and 16 h during infection of HBV genotype A (left graph) or C (right graph) as shown in Fig. 1A. HBV infection was monitored with cellular HBV DNA at 12 days after the infection as Fig. 1C.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814766&req=5

Figure 7: Antiviral activity of AID was specific to HBV.A, Huh-7.5.1 cells were pretreated with IL-1β, TNFα, or IFNα for 3 h or left untreated and then coincubated with HCV for 4 h. After washing HCV and cytokines and culturing the cells with normal medium for 72 h, the infectivity of HCV (left panel) as well as HCV core protein (right panel) in the medium was quantified. B, HepaRG cells were treated with IL-1β or heparin or left untreated for 3 h prior to and 16 h during infection of HBV genotype A (left graph) or C (right graph) as shown in Fig. 1A. HBV infection was monitored with cellular HBV DNA at 12 days after the infection as Fig. 1C.
Mentions: HBV used in this study was mainly derived from HepAD38 cells, which is classified as genotype D (38). Media from HepAD38 cells at days 7–31 post-induction of HBV by depletion of tetracycline were recovered every 3 days. Media were cleared through a 0.45-μm filter and precipitated with 10% PEG8000 and 2.3% NaCl. The precipitates were washed and resuspended with medium at ∼200-fold concentration. The HBV DNA was quantified by real time PCR. HBV genotype A and C in Fig. 7B was recovered from the media of HepG2 cells transfected with the plasmid pHBV/Aeus and pHBV/C-AT (41).

Bottom Line: This effect was mediated by activation of the NF-κB signaling pathway.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.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.

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.

Show MeSH
Related in: MedlinePlus