The GTPase Domain of MX2 Interacts with HIV-1 Capsid Enabling Its Short Isoform to Moderate Antiviral Restriction

Abstract

Myxovirus resistance 2 (MX2/MXB) is an interferon (IFN)-induced HIV-1 restriction factor that inhibits viral nuclear DNA accumulation. The amino-terminal domain of MX2 binds the viral capsid and is essential for inhibition. Using in vitro assembled Capsid-Nucleocapsid (CANC) complexes as a surrogate for the HIV-1 capsid lattice, we reveal that the GTPase (G) domain of MX2 contains a second, independent capsid binding site. The importance of this interaction was addressed in a series of competition assays using the naturally occurring non-antiviral short isoform of MX2 that lacks the amino-terminal 25 amino acids. Specifically, we show that the G domain enhances MX2 function, and that the foreshortened isoform acts as a functional suppressor of the full-length protein in a G domain-dependent manner. The interaction of MX2 with its HIV-1 capsid substrate is therefore multi-faceted: there are dual points of contact which, together with protein oligomerization, contribute to the complexity of MX2 regulation.

Keywords: HIV-­1, MX2, capsid, GTPase domain, short isoform, antiviral activity