MX2 is an interferon-induced inhibitor of HIV-1 infection

• Published in: Nature (London) Vol. 502; no. 7472; pp. 563 - 566
• Main Authors: Kane, Melissa, Yadav, Shalini S., Bitzegeio, Julia, Kutluay, Sebla B., Zang, Trinity, Wilson, Sam J., Schoggins, John W., Rice, Charles M., Yamashita, Masahiro, Hatziioannou, Theodora, Bieniasz, Paul D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.10.2013; Nature Publishing Group
• Subjects: 38/109; 38/39; 631/326/596/2556; Active Transport, Cell Nucleus; Antiretroviral agents; Capsid - metabolism; Cell Division; Cell Line; Cell Nucleus - metabolism; Cell Nucleus - virology; Cells, Cultured; Deoxyribonucleic acid; DNA; Gene expression; Genetic aspects; Health aspects; HIV infection; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - metabolism; HIV Infections - prevention & control; HIV-1 - immunology; HIV-1 - physiology; Host-parasite relationships; Humanities and Social Sciences; Humans; Interferon; Interferon-alpha - immunology; letter; multidisciplinary; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Myxovirus Resistance Proteins - genetics; Myxovirus Resistance Proteins - metabolism; Physiological aspects; Plasmids; Proteins; Reverse Transcription; RNA Interference; Science; Transcriptome; Virus Replication; Viruses; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12653

MX2 is shown to be an interferon-induced inhibitor of HIV-1 infection, and this antiviral activity may involve the inhibition of nuclear import of subviral complexes. Human MX2 protein is an HIV-1 resistance factor Two groups report in this issue of Nature that the human interferon-induced GTP-binding protein MX2 is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) and a number of other lentiviruses. For some years it had been known that the related protein MX1 can inhibit HIV-1 replication in humans, but MX2 was thought to be devoid of antiviral activity. The anti-HIV-1 action of MX2 is much less dependent on GTPase activity than is the broader antiviral activity of MX1, pointing to possible mechanistic differences between them. HIV-1 replication can be inhibited by type I interferon (IFN), and the expression of a number of gene products with anti-HIV-1 activity is induced by type I IFN 1 , 2 . However, none of the known antiretroviral proteins can account for the ability of type I IFN to inhibit early, preintegration phases of the HIV-1 replication cycle in human cells 3 , 4 . Here, by comparing gene expression profiles in cell lines that differ in their ability to support the inhibitory action of IFN-α at early steps of the HIV-1 replication cycle, we identify myxovirus resistance 2 (MX2) as an interferon-induced inhibitor of HIV-1 infection. Expression of MX2 reduces permissiveness to a variety of lentiviruses, whereas depletion of MX2 using RNA interference reduces the anti-HIV-1 potency of IFN-α. HIV-1 reverse transcription proceeds normally in MX2-expressing cells, but 2-long terminal repeat circular forms of HIV-1 DNA are less abundant, suggesting that MX2 inhibits HIV-1 nuclear import, or destabilizes nuclear HIV-1 DNA. Consistent with this notion, mutations in the HIV-1 capsid protein that are known, or suspected, to alter the nuclear import pathways used by HIV-1 confer resistance to MX2, whereas preventing cell division increases MX2 potency. Overall, these findings indicate that MX2 is an effector of the anti-HIV-1 activity of type-I IFN, and suggest that MX2 inhibits HIV-1 infection by inhibiting capsid-dependent nuclear import of subviral complexes.