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Roles of APOBEC3 in hepatitis B virus (HBV) infection and hepatocarcinogenesis.

ABSTRACT: APOBEC3 (A3) cytidine deaminases inhibit hepatitis B virus (HBV) infection and play vital roles in maintaining a variety of biochemical processes, including the regulation of protein expression and innate immunity. Emerging evidence indicates that the deaminated deoxycytidine biochemical activity of A3 proteins in single-stranded DNA makes them a double-edged sword. These enzymes can cause cellular genetic mutations at replication forks or within transcription bubbles, depending on the physiological state of the cell and the phase of the cell cycle. Under pathological conditions, aberrant expression of A3 genes with improper deaminase activity regulation may threaten genomic stability and eventually lead to cancer development. This review attempted to summarize the antiviral activities and underlying mechanisms of A3 editing enzymes in HBV infections. Moreover, the correlations between A3 genes and hepatocarcinogenesis were also elucidated.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8806738 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Roles of APOBEC3 in hepatitis B virus (HBV) infection and hepatocarcinogenesis.

Zhang Yuan Y Chen Xiaorong X Cao Yajuan Y Yang Zongguo Z

Bioengineered 20211201 1

APOBEC3 (A3) cytidine deaminases inhibit hepatitis B virus (HBV) infection and play vital roles in maintaining a variety of biochemical processes, including the regulation of protein expression and innate immunity. Emerging evidence indicates that the deaminated deoxycytidine biochemical activity of A3 proteins in single-stranded DNA makes them a double-edged sword. These enzymes can cause cellular genetic mutations at replication forks or within transcription bubbles, depending on the physiolog ...[more]

PMID: 34043485

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Project description:The same entry pathway is shared by HBV and HDV. Both viruses attach to hepatocytes via heparansulfate proteoglycan and utilize sodium taurocholate co-transporting polypeptide (NTCP) for a specifc entry. This specific entry step is inhibited by Myrcludex B, a 47-aa lipopeptide myristoylated at the N-terminus. Here we compared the cellular response in the gene expression level triggerred by both viruses. The microarray data shows that HBV infection leads to a silent response but HDV infection triggers high level of innate response such as inteferon-stimulated genes (ISG) expression. Moreover, the response depends on the hepatic cell lines used for infection. Compared to HepG2 cells, HuH7 can not induce ISG even infected by HDV. Abstract of manuscript: Background & aims: Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. Methods: HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. Results: Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2NTCP cells. HDV strongly activated IFN-β and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I or TLR3 knock-down, but were almost completely abolished upon MDA5 depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in Huh7.5NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2NTCP and HepaRGNTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. Conclusions: Active replication of HDV induces an IFN-β/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN activated state.

Dataset Information

Roles of APOBEC3 in hepatitis B virus (HBV) infection and hepatocarcinogenesis.

Publications

Roles of APOBEC3 in hepatitis B virus (HBV) infection and hepatocarcinogenesis.

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