The myxovirus resistance 2 (MX2)
protein of humans has been identified recently as an
interferon (IFN)-inducible inhibitor of human immunodeficiency virus type 1 (HIV-1) that acts at a late postentry step of
infection to prevent the nuclear accumulation of viral
cDNA (C. Goujon et al., Nature 502:559-562, 2013, http://dx.doi.org/10.1038/nature12542; M. Kane et al., Nature 502:563-566, 2013, http://dx.doi.org/10.1038/nature12653; Z. Liu et al., Cell Host Microbe 14:398-410, 2013, http://dx.doi.org/10.1016/j.chom.2013.08.015). In contrast, the closely related
human MX1 protein, which suppresses
infection by a range of
RNA and DNA viruses (such as influenza A virus [FluAV]), is ineffective against HIV-1. Using a panel of engineered chimeric MX1/2
proteins, we demonstrate that the amino-terminal 91-amino-acid domain of MX2 confers full anti-HIV-1 function when transferred to the amino terminus of MX1, and that this fusion
protein retains full anti-FluAV activity. Confocal microscopy experiments further show that this MX1/2 fusion, similar to MX2 but not MX1, can localize to the nuclear envelope (NE), linking HIV-1 inhibition with MX accumulation at the NE. MX
proteins are
dynamin-like
GTPases, and while MX1
antiviral function requires
GTPase activity, neither MX2 nor MX1/2 chimeras require this attribute to inhibit HIV-1. This key discrepancy between the characteristics of MX1- and MX2-mediated viral resistance, together with previous observations showing that the L4 loop of the stalk domain of MX1 is a critical determinant of viral substrate specificity, presumably reflect fundamental differences in the mechanisms of
antiviral suppression. Accordingly, we propose that further comparative studies of MX
proteins will help illuminate the molecular basis and subcellular localization requirements for implementing the noted diversity of virus inhibition by MX
proteins.
IMPORTANCE:
Interferon (IFN) elicits an
antiviral state in cells through the induction of hundreds of IFN-stimulated genes (ISGs). The
human MX2 protein has been identified as a key effector in the suppression of HIV-1
infection by IFN. Here, we describe a molecular genetic approach, using a collection of chimeric MX
proteins, to identify protein domains of MX2 that specify HIV-1 inhibition. The amino-terminal 91-amino-acid domain of human MX2 confers HIV-1 suppressor capabilities upon human and mouse MX
proteins and also promotes
protein accumulation at the nuclear envelope. Therefore, these studies correlate the cellular location of MX
proteins with anti-HIV-1 function and help establish a framework for future mechanistic analyses of MX-mediated virus control.