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Open Access Publications from the University of California

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

  • Author(s): Heaton, NS
  • Moshkina, N
  • Fenouil, R
  • Gardner, TJ
  • Aguirre, S
  • Shah, PS
  • Zhao, N
  • Manganaro, L
  • Hultquist, JF
  • Noel, J
  • Sachs, DH
  • Hamilton, J
  • Leon, PE
  • Chawdury, A
  • Tripathi, S
  • Melegari, C
  • Campisi, L
  • Hai, R
  • Metreveli, G
  • Gamarnik, AV
  • García-Sastre, A
  • Greenbaum, B
  • Simon, V
  • Fernandez-Sesma, A
  • Krogan, NJ
  • Mulder, LCF
  • van Bakel, H
  • Tortorella, D
  • Taunton, J
  • Palese, P
  • Marazzi, I
  • et al.

© 2016 Elsevier Inc. 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.

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