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.

Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection / N.S. Heaton, N. Moshkina, R. Fenouil, T.J. Gardner, S. Aguirre, P.S. Shah, N. Zhao, L. Manganaro, J.F. Hultquist, J. Noel, D.H. Sachs, J. Hamilton, P.E. Leon, A. Chawdury, S. Tripathi, C. Melegari, L. Campisi, R. Hai, G. Metreveli, A.V. Gamarnik, A. Garcia-Sastre, B. Greenbaum, V. Simon, A. Fernandez-Sesma, N.J. Krogan, L.C.F. Mulder, H. van Bakel, D. Tortorella, J. Taunton, P. Palese, I. Marazzi. - In: IMMUNITY. - ISSN 1074-7613. - 44:1(2016), pp. 46-58. [10.1016/j.immuni.2015.12.017]

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

L. Manganaro;
2016

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.
Dengue Virus; HIV; Host-Parasite Interactions; Humans; Immunoprecipitation; Influenza A virus; Mass Spectrometry; Protein Folding; Proteomics; Virus Replication; Models, Theoretical
Settore BIO/19 - Microbiologia Generale
Article (author)
File in questo prodotto:
File Dimensione Formato  
Heaton et al 2016.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.19 MB
Formato Adobe PDF
2.19 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/886484
Citazioni
  • ???jsp.display-item.citation.pmc??? 67
  • Scopus 81
  • ???jsp.display-item.citation.isi??? 84
social impact