Human MxB Protein Is a Pan-herpesvirus Restriction Factor

Abstract

Herpesvirus infections are highly prevalent in the human population and persist for life. They are often acquired subclinically but potentially progress to life-threatening diseases in immunocompromised individuals. The interferon system is indispensable for the control of herpesviral replication. However, the responsible antiviral effector mechanisms are not well characterized. The type I interferon-induced, human myxovirus resistance 2 () gene product MxB, a dynamin-like large GTPase, has recently been identified as a potent inhibitor of HIV-1. We now show that MxB also interferes with an early step of herpesvirus replication, affecting alpha-, beta-, and gammaherpesviruses before or at the time of immediate early gene expression. Defined MxB mutants influencing GTP binding and hydrolysis revealed that the effector mechanism against herpesviruses is thoroughly different from that against HIV-1. Overall, our findings demonstrate that MxB serves as a broadly acting intracellular restriction factor that controls the establishment of not only retrovirus but also herpesvirus infection of all three subfamilies. Human herpesviruses pose a constant threat to human health. Reactivation of persisting herpesvirus infections, particularly in immunocompromised individuals and the elderly, can cause severe diseases, such as zoster, pneumonia, encephalitis, or cancer. The interferon system is relevant for the control of herpesvirus replication as exemplified by fatal disease outcomes in patients with primary immunodeficiencies. Here, we describe the interferon-induced, human gene product MxB as an efficient restriction factor of alpha-, beta-, and gammaherpesviruses. MxB has previously been described as an inhibitor of HIV-1. Importantly, our mutational analyses of MxB reveal an antiviral mechanism of herpesvirus restriction distinct from that against HIV-1. Thus, the dynamin-like MxB GTPase serves as a broadly acting intracellular restriction factor that controls retrovirus as well as herpesvirus infections.

Interferon-Independent Innate Responses to Cytomegalovirus

“…HSV-1 and MCMV inhibition manifested in a similar way to that of HIV-1, a block in the delivery of viral genome to the nucleus (151). However, in terms of the regions of protein at play, this mechanism was found to differ substantially with a requirement for GTP binding but not GTP hydrolysis (152,153). Knockdown of MxB has also been implicated in stalling cell cycle progression (147) and it has been suggested that the HCMV virion protein pUL69 that contributes to the cell cycle arrest (154) does so via an interaction with MxB (155).…”

“…On the other hand, MxB localizes to the cytoplasmic face of nuclear pores (147) and is able to inhibit HIV-1 replication by blocking nuclear viral genome accumulation (148,149). Both MxA and MxB are highly upregulated by HCMV infection (73,150) and it has recently been discovered that MxB overexpression inhibits replication of HSV-1, HSV-2, Kaposi's sarcoma-associated herpesvirus (KSHV), MCMV, and HCMV (151,152). HSV-1 and MCMV inhibition manifested in a similar way to that of HIV-1, a block in the delivery of viral genome to the nucleus (151).…”

Mapping Viral Susceptibility Loci in Mice

“…For example, human Mx1 is cytoplasmic and inhibits a variety of viruses, including, but not limited to, influenza A, measles, VSV, and HBV (82) (Figure 4). Human Mx2, on the other hand, is localized at the nuclear pore and inhibits human immunodeficiency virus (HIV) and herpesviruses (83)(84)(85)(86)(87). These proteins generally inhibit early stages in the viral life cycle by targeting subviral structures such as the nucleocapsid or core, and, except in the case of inhibition of HIV infection by Mx2, restriction by these proteins requires GTP hydrolysis (82) (Figure 4).…”

Tuning the Orchestra: HCMV vs. Innate Immunity

“…The antiviral activity of Mx against herpesviruses is somewhat more controversial. Indeed, while it has recently been demonstrated a pan-herpesvirus restriction activity for MxB against IE viral gene expression, the precise mechanisms it relies on has not yet been fully clarified (Schilling et al, 2018). The most consistent hypothesis is that of a direct action of MxB during the uncoating process aimed at targeting viral capsids or components of the nuclear pore complexes, similarly to what happens during HSV-1 infection (Crameri et al, 2018).…”