King's College London

Research portal

Oligomerization requirements for MX2 mediated suppression of HIV-1 infection

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)22-32
JournalJournal of Virology
Volume90
Issue number1
Early online date7 Oct 2015
DOIs
StatePublished - Jan 2016

Documents

King's Authors

Abstract

Human myxovirus resistance 2 (MX2/MXB) is an interferon-stimulated gene (ISG), and was recently identified as a late post-entry suppressor of human immunodeficiency virus type-1 (HIV-1) infection, inhibiting nuclear accumulation of viral cDNAs. Although the HIV-1 capsid (CA) protein is believed to be the viral determinant of MX2 mediated inhibition, the precise mechanism of anti-viral action remains unclear. The MX family of dynamin-like GTPases also includes MX1/MXA, a well-studied inhibitor of a range of RNA and DNA viruses including influenza A virus (FLUAV) and hepatitis B virus but not retroviruses. MX1 and MX2 are closely related, and share a similar domain architecture and structure. However, MX2 possesses an extended N-terminus that is essential for anti-viral function and confers anti-HIV-1 activity on MX1 (MX1(NMX2)). Higher order oligomerization is required for the anti-viral activity of MX1 against FLUAV, with current models proposing that MX1 forms ring structures that constrict around viral nucleoprotein complexes. Here, we performed structure-function studies to investigate the requirements for oligomerization of both MX2 and chimeric MX1(NMX2) for the inhibition of HIV-1 infection. The oligomerization state of mutated proteins with amino acid substitutions at multiple putative oligomerization interfaces was assessed using a combination of covalent cross-linking, and co-immunoprecipitation. We show that, while monomeric MX2 and MX1(NMX2) mutants are not anti-viral, higher order oligomerization does not appear to be required for full anti-viral activity of either protein. We propose that lower-order oligomerization of MX2 is sufficient for effective inhibition of HIV-1.

IMPORTANCE Interferon (IFN) plays an important role in the control of virus replication during acute infection in vivo. Recently, cultured cell experiments identified human myxovirus resistance 2 (MX2/MXB) as a key effector in the interferon mediated post-entry block to human immunodeficiency virus type-1 (HIV-1) infection. MX2 is a member of a family of large dynamin-like GTPases that includes MX1/MXA, a closely related interferon inducible inhibitor of several viruses including influenza A virus (FLUAV), but not HIV-1. MX GTPases form higher-order oligomeric structures, and the oligomerization of MX1 is required for inhibitory activity against many of its viral targets. Through structure-function studies, we report that monomeric mutants of MX2 do not inhibit HIV-1. However, in contrast to MX1, oligomerization beyond dimer assembly does not seem to be required for the anti-viral activity of MX2 implying that fundamental differences exist between the anti-viral mechanisms employed by these closely related proteins.

Download statistics

No data available

View graph of relations

© 2015 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454