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Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import.
Sci Rep. 2016 Mar 18; 6:23138.SR

Abstract

To establish a new lineage in the human population, avian influenza A viruses (AIV) must overcome the intracellular restriction factor MxA. Partial escape from MxA restriction can be achieved when the viral nucleoprotein (NP) acquires the critical human-adaptive amino acid residues 100I/V, 283P, and 313Y. Here, we show that introduction of these three residues into the NP of an avian H5N1 virus renders it genetically unstable, resulting in viruses harboring additional single mutations, including G16D. These substitutions restored genetic stability yet again yielded viruses with varying degrees of attenuation in mammalian and avian cells. Additionally, most of the mutant viruses lost the capacity to escape MxA restriction, with the exception of the G16D virus. We show that MxA escape is linked to attenuation by demonstrating that the three substitutions promoting MxA escape disturbed intracellular trafficking of incoming viral ribonucleoprotein complexes (vRNPs), thereby resulting in impaired nuclear import, and that the additional acquired mutations only partially compensate for this import block. We conclude that for adaptation to the human host, AIV must not only overcome MxA restriction but also an associated block in nuclear vRNP import. This inherent difficulty may partially explain the frequent failure of AIV to become pandemic.

Authors+Show Affiliations

Institute of Virology, University Medical Center Freiburg, D-79104 Freiburg, Germany.Institute of Virology, University Medical Center Freiburg, D-79104 Freiburg, Germany.Institute of Virology, University Medical Center Freiburg, D-79104 Freiburg, Germany.Institute of Virology, University Medical Center Freiburg, D-79104 Freiburg, Germany.Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, 17493 Greifswald-Insel Riems, Germany.Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, 17493 Greifswald-Insel Riems, Germany.Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA.Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, 17493 Greifswald-Insel Riems, Germany.Institute of Virology, University Medical Center Freiburg, D-79104 Freiburg, Germany.Institute of Virology, University Medical Center Freiburg, D-79104 Freiburg, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26988202

Citation

Götz, Veronika, et al. "Influenza a Viruses Escape From MxA Restriction at the Expense of Efficient Nuclear vRNP Import." Scientific Reports, vol. 6, 2016, p. 23138.
Götz V, Magar L, Dornfeld D, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138.
Götz, V., Magar, L., Dornfeld, D., Giese, S., Pohlmann, A., Höper, D., Kong, B. W., Jans, D. A., Beer, M., Haller, O., & Schwemmle, M. (2016). Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Scientific Reports, 6, 23138. https://doi.org/10.1038/srep23138
Götz V, et al. Influenza a Viruses Escape From MxA Restriction at the Expense of Efficient Nuclear vRNP Import. Sci Rep. 2016 Mar 18;6:23138. PubMed PMID: 26988202.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. AU - Götz,Veronika, AU - Magar,Linda, AU - Dornfeld,Dominik, AU - Giese,Sebastian, AU - Pohlmann,Anne, AU - Höper,Dirk, AU - Kong,Byung-Whi, AU - Jans,David A, AU - Beer,Martin, AU - Haller,Otto, AU - Schwemmle,Martin, Y1 - 2016/03/18/ PY - 2015/11/15/received PY - 2016/03/01/accepted PY - 2016/3/19/entrez PY - 2016/3/19/pubmed PY - 2017/1/26/medline SP - 23138 EP - 23138 JF - Scientific reports JO - Sci Rep VL - 6 N2 - To establish a new lineage in the human population, avian influenza A viruses (AIV) must overcome the intracellular restriction factor MxA. Partial escape from MxA restriction can be achieved when the viral nucleoprotein (NP) acquires the critical human-adaptive amino acid residues 100I/V, 283P, and 313Y. Here, we show that introduction of these three residues into the NP of an avian H5N1 virus renders it genetically unstable, resulting in viruses harboring additional single mutations, including G16D. These substitutions restored genetic stability yet again yielded viruses with varying degrees of attenuation in mammalian and avian cells. Additionally, most of the mutant viruses lost the capacity to escape MxA restriction, with the exception of the G16D virus. We show that MxA escape is linked to attenuation by demonstrating that the three substitutions promoting MxA escape disturbed intracellular trafficking of incoming viral ribonucleoprotein complexes (vRNPs), thereby resulting in impaired nuclear import, and that the additional acquired mutations only partially compensate for this import block. We conclude that for adaptation to the human host, AIV must not only overcome MxA restriction but also an associated block in nuclear vRNP import. This inherent difficulty may partially explain the frequent failure of AIV to become pandemic. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26988202/full_citation L2 - https://doi.org/10.1038/srep23138 DB - PRIME DP - Unbound Medicine ER -