Human MxB Inhibits the Replication of Hepatitis C Virus

Abstract

Type I interferon (IFN) inhibits viruses by inducing the expression of antiviral proteins. The IFN-induced myxovirus resistance B (MxB) protein has been reported to inhibit a limited number of viruses, including HIV-1 and herpesviruses, but its antiviral coverage remains to be explored further. Here we show that MxB interferes with RNA replication of hepatitis C virus (HCV) and significantly inhibits viral replication in a cyclophilin A (CypA)-dependent manner. Our data further show that MxB interacts with the HCV protein NS5A, thereby impairing NS5A interaction with CypA and NS5A localization to the endoplasmic reticulum, two events essential for HCV RNA replication. Interestingly, we found that MxB significantly inhibits two additional CypA-dependent viruses of the Flaviviridae family, namely, Japanese encephalitis virus and dengue virus, suggesting a potential link between virus dependence on CypA and virus susceptibility to MxB inhibition. Collectively, these data have identified MxB as a key factor behind IFN-mediated suppression of HCV infection, and they suggest that other CypA-dependent viruses may also be subjected to MxB restriction. IMPORTANCE Viruses of the Flaviviridae family cause major illness and death around the world and thus pose a great threat to human health. Here we show that IFN-inducible MxB restricts several members of the Flaviviridae, including HCV, Japanese encephalitis virus, and dengue virus. This finding not only suggests an active role of MxB in combating these major pathogenic human viruses but also significantly expands the antiviral spectrum of MxB. Our study further strengthens the link between virus dependence on CypA and susceptibility to MxB restriction and also suggests that MxB may employ a common mechanism to inhibit different viruses. Elucidating the antiviral functions of MxB advances our understanding of IFN-mediated host antiviral defense and may open new avenues to the development of novel antiviral therapeutics.

Subcellular Localization of MxB Determines Its Antiviral Potential against Influenza A Virus

“…The subcellular localization determines in part the antiviral specificity of Mx proteins (4,5). MxB has recently been shown to inhibit the replication of primate (non-human and human) lentiviruses, herpesviruses, and cyclophilin Adependent flaviviruses (6)(7)(8)(9)(10)(11)(12). Mammalian Mx proteins accumulate in different subcellular compartments.…”

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

“…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].…”

The anti-viral dynamin family member MxB participates in mitochondrial integrity

“…MxB also assembles into polymeric structures 28 and was originally found to associate with nuclear pores where it was predicted to restrict the access of a viral genome to the host transcriptional machinery 29 . MxB has been described to bind to the HIV-1 genome, while impairing its chromosomal integration 24,30,31 , and recently has been identified as a key factor behind IFN-mediated suppression of hepatitis C virus infection 32 .…”