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

HEATON, NICHOLAS S.; MOSHKINA, NATASHA; FENOUIL, ROMAIN; GARDNER, THOMAS J.; AGUIRRE, SEBASTIAN; SHAH, PRIYA S.; ZHAO, NAN; MANGANARO, LARA; HULTQUIST, JUDD F.; NOEL, JUSTINE; SACHS, DAVID H.; HAMILTON, JENNIFER; LEON, PAUL E.; CHAWDURY, AMIT; TRIPATHI, SHASHANK; MELEGARI, CAMILLA; CAMPISI, LAURA; HAI, RONG; METREVELI, GIORGI; GAMARNIK, ANDREA V.; GARCÍA-SASTRE, ADOLFO; GREENBAUM, BENJAMIN; SIMON, VIVIANA; FERNANDEZ-SESMA, ANA; KROGAN, NEVAN J.; MULDER, LUBBERTUS C.F.; VAN BAKEL, HARM; TORTORELLA, DOMENICO; TAUNTON, JACK; PALESE, PETER; MARAZZI, IVAN

IMMUNITY

CELL PRESS

Año: 2016 vol. 44 p. 46 - 58

1074-7613

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.