Human MX2/MxB: a Potent Interferon-Induced Postentry Inhibitor of Herpesviruses and HIV-1

Abstract

Interferons limit viral replication by inducing intracellular restriction factors, such as the GTPase MxB (also designated MX2), which inhibits HIV-1 and, as recently shown, herpesviruses. Inhibition of these viruses occurs at ill-defined steps after viral entry and requires formation of MxB dimers or oligomers, but GTP hydrolysis is needed only for blocking herpesviruses. Together with previous findings on related MxA, the new research on MxB highlights the mechanistic diversity by which MX proteins interfere with viral replication.

Keywords: HIV-1; MX2; MxB; herpesviruses; interferons.

FIG 1

Structure of human MxB. (A) Location of known domains in full-length MxB and its N-terminally truncated isoform [MxB_(26–715)] that is translated from the second AUG initiation codon (23). NLS, nuclear localization signal; BSE, bundle signaling element. (B) Predicted 3-dimensional structure of MxB (Protein Data Bank accession number 4WHJ) (26). The structure of the NLS-containing N terminus is unknown; the L4 loop is intrinsically unstructured. (C) Predicted structure of the antivirally active MxB dimer deduced from crystal structural (26) and CryoEM (25) analyses.

FIG 2

MxB inhibits postentry steps of the HSV-1 and HIV-1 life cycles. (A) MxB inhibits nuclear delivery of herpesviral DNA. MxB dimers accumulating at the nuclear membrane are the minimal functional units that inhibit the docking of viral capsid to the nuclear pore complex (NPC). Since no direct interactions between MxB dimers and herpesviral nucleocapsids were reported, an indirect mode of action via undefined cellular factors is likely. The antiherpesvirus activity of MxB is GTPase dependent. (B) MxB dimers bind the nucleocapsid of HIV-1, thereby influencing viral capsid interaction with nucleoporins (Nups). Dependent on cell type and cell cycle progression, such interactions may inhibit the nuclear import of the viral preintegration complex (PIC) and the integration of proviral DNA into the host cell genome. The GTPase activity of MxB is not required for HIV-1 inhibition.