Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection

Nicholas S. Heaton, Natasha Moshkina, Romain Fenouil, Thomas J. Gardner, Sebastian Aguirre, Priya S. Shah, Nan Zhao, Lara Manganaro, Judd F. Hultquist, Justine Noel, David H. Sachs, Jennifer Hamilton, Paul E. Leon, Amit Chawdury, Shashank Tripathi, Camilla Melegari, Laura Campisi, Rong Hai, Giorgi Metreveli, Andrea V. GamarnikAdolfo García-Sastre, Benjamin Greenbaum, Viviana Simon, Ana Fernandez-Sesma, Nevan J. Krogan, Lubbertus C.F. Mulder, Harm van Bakel, Domenico Tortorella, Jack Taunton, Peter Palese, Ivan Marazzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling and genetic and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication, we have identified targetable host factors for broad-spectrum antiviral therapies. Viruses are obligate parasites dependent on the host cell machinery. Using infection-based proteomics, biochemistry, and mathematical modeling, Marazzi and colleagues reveal that targeting host factors controlling essential cellular functions can provide broad-spectrum antiviral effects. Loss-of-function and chemical inhibition of one such factor, Sec61, inhibited influenza, HIV, and dengue virus replication.

Original languageEnglish (US)
Pages (from-to)46-58
Number of pages13
JournalImmunity
Volume44
Issue number1
DOIs
StatePublished - Jan 19 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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