Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication

Wang, Yongxiang; Niklasch, Matthias; Liu, Tiantian; Wang, Yang; Shi, Bisheng; Yuan, Weixing; Baumert, Thomas F.; Yuan, Zhenghong; Tong, Shuping; Nassal, Michael; Wen, Yiping

doi:10.1016/j.jhep.2019.12.009

Cited by 71 publications

(66 citation statements)

References 77 publications

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“…Thus, the mechanisms underlying PEG-IFN targeting of HBV primarily involve harnessing the host innate immune system to target viral replication and replicative intermediates through multi-faceted approaches [ 15 ]. Indeed, studies have demonstrated the capability of IFN in inducing expression and activation of innate anti-viral interferon stimulated genes/proteins, which serves to effectively inhibit HBV replication [ 16 , 17 , 18 , 19 , 20 , 21 ]. Activation of interferon stimulated genes (ISGs) including, but not limited to, the apolipoprotein B mRNA editing enzyme (APOBEC)3 family, MX2, ISG20, and the TRIM family have been described with innate anti-HBV effects [ 16 , 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, studies have demonstrated the capability of IFN in inducing expression and activation of innate anti-viral interferon stimulated genes/proteins, which serves to effectively inhibit HBV replication [ 16 , 17 , 18 , 19 , 20 , 21 ]. Activation of interferon stimulated genes (ISGs) including, but not limited to, the apolipoprotein B mRNA editing enzyme (APOBEC)3 family, MX2, ISG20, and the TRIM family have been described with innate anti-HBV effects [ 16 , 17 , 18 , 19 , 20 , 21 ]. Furthermore, studies have reported the capability of IFNα therapy to inhibit viral replication and suppress HBV gene expression through epigenetic modulation of the HBV cccDNA [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

2020

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Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

2020

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“…Human Myxovirus resistance protein 2 (Mx2/MxB), a member of the dynamin-like large GTPases that belong to the dynamin superfamily, was originally found to regulate cell-cycle progression and cytoplasmic-nuclear transport [1], but recently was demonstrated to inhibit the infection of various viruses, including HIV-1 [2][3][4], Herpesviruses [5,6], HTNV [7], HCV [8], HBV [9] and other lentiviruses such as SIV, EIAV and FIV [2]. Human MxB was reported to target the HIV-1 capsid protein (CA) after cell entry [10][11][12][13], to prevent uncoating [14], nuclear import of the viral pre-integration complex (PIC, composed of viral components include viral DNA, integrase (IN), nucleocapsid (NC), matrix (MA), viral protein R (Vpr), and reverse transcriptase (RT); several host proteins including lens epithelium-derived growth factor (LEDGF/p75), barrier-to-autointegration factor (BAF), and integrase interactor 1 (INI1) [15,16]) and subsequent chromosomal integration of the proviral DNA into the host genome, but did not affect reverse transcription [2-4, 17, 18].…”

Section: Introductionmentioning

confidence: 99%

MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6

et al. 2020

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Background: The human myxovirus resistance 2 (Mx2/MxB) protein was originally found to regulate cytoplasmicnuclear transport but was recently reported to restrict HIV-1 replication by binding to HIV-1 capsid (CA), preventing uncoating, the nuclear import of pre-integration complex (PIC) and viral DNA integration. This work explores the mechanisms of MxB-mediated HIV-1 inhibition. Results: We demonstrated that MxB represses NUP358-mediated PIC nuclear import and HIV-1 replication. Moreover, MxB's effects on PIC nuclear import and HIV-1 replication depend critically on cofactor cleavage and polyadenylation specificity factor subunit 6 (CPSF6). MxB binds nucleoporin NUP358, blocks NUP358-CA interaction, thereby impeding the nuclear import of HIV-1 PIC with CPSF6 binding to PIC. More intriguingly, CPSF6's role in nuclear import depends on MxB, being a facilitator of HIV-1 nuclear import on its own, but becoming an inhibitor when MxB is present. Conclusions: Our work establishes that MxB impedes the NUP358-mediated HIV-1 nuclear import and viral replication cooperatively with CPSF6.

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“…Human Myxovirus resistance proteins 1 and 2, MX1 and MX2 (also named MxA and MxB) are members of this family and possess potent antiviral activity against a broad range of viruses [170]. MX1 is best known for its ability to inhibit IAV infection, but it can also inhibit a wide range of positive-or negative-single stranded or double stranded RNA viruses as well as certain DNA viruses [170], and MX2 inhibits HIV-1, Herpesviruses, HCV and HBV [171][172][173][174][175][176][177]. The MX genes were first discovered in mice (MmMx1), with the serendipitous observation that the A2G mice strain were resistant to IAV infection whereas most inbred laboratory strains, lacking a functional MmMx1 locus, were highly susceptible [178].…”

Section: Restriction Factors Inhibiting Viral Genome Replicationmentioning

confidence: 99%

Mammalian and Avian Host Cell Influenza A Restriction Factors

McKellar

Rebendenne

Wencker

et al. 2021

Viruses

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The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic.

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Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication

Cited by 71 publications

References 77 publications

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6

Mammalian and Avian Host Cell Influenza A Restriction Factors

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