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

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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.

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Heaton, N. S., Moshkina, N., Fenouil, R., Gardner, T. J., Aguirre, S., Shah, P. S., … Marazzi, I. (2016). Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. Immunity, 44(1), 46–58. https://doi.org/10.1016/j.immuni.2015.12.017

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