Tags

Type your tag names separated by a space and hit enter

Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication.
Antiviral Res. 2013 Dec; 100(3):662-72.AR

Abstract

Targeting host responses to invading viruses has been the focus of recent antiviral research. Venezuelan Equine Encephalitis Virus (VEEV) is able to modulate host transcription and block nuclear trafficking at least partially due to its capsid protein forming a complex with the host proteins importin α/β1 and CRM1. We hypothesized that disrupting the interaction of capsid with importin α/β1 or the interaction of capsid with CRM1 would alter capsid localization, thereby lowering viral titers in vitro. siRNA mediated knockdown of importin α, importin β1, and CRM1 altered capsid localization, confirming their role in modulating capsid trafficking. Mifepristone and ivermectin, inhibitors of importin α/β-mediated import, were able to reduce nuclear-associated capsid, while leptomycin B, a potent CRM1 inhibitor, confined capsid to the nucleus. In addition to altering the level and distribution of capsid, the three inhibitors were able to reduce viral titers in a relevant mammalian cell line with varying degrees of efficacy. The inhibitors were also able to reduce the cytopathic effects associated with VEEV infection, hinting that nuclear import inhibitors may be protecting cells from apoptosis in addition to disrupting the function of an essential viral protein. Our results confirm that VEEV uses host importins and exportins during part of its life cycle. Further, it suggests that temporarily targeting host proteins that are hijacked for use by viruses is a viable antiviral therapy.

Authors+Show Affiliations

National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24161512

Citation

Lundberg, Lindsay, et al. "Nuclear Import and Export Inhibitors Alter Capsid Protein Distribution in Mammalian Cells and Reduce Venezuelan Equine Encephalitis Virus Replication." Antiviral Research, vol. 100, no. 3, 2013, pp. 662-72.
Lundberg L, Pinkham C, Baer A, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100(3):662-72.
Lundberg, L., Pinkham, C., Baer, A., Amaya, M., Narayanan, A., Wagstaff, K. M., Jans, D. A., & Kehn-Hall, K. (2013). Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Research, 100(3), 662-72. https://doi.org/10.1016/j.antiviral.2013.10.004
Lundberg L, et al. Nuclear Import and Export Inhibitors Alter Capsid Protein Distribution in Mammalian Cells and Reduce Venezuelan Equine Encephalitis Virus Replication. Antiviral Res. 2013;100(3):662-72. PubMed PMID: 24161512.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. AU - Lundberg,Lindsay, AU - Pinkham,Chelsea, AU - Baer,Alan, AU - Amaya,Moushimi, AU - Narayanan,Aarthi, AU - Wagstaff,Kylie M, AU - Jans,David A, AU - Kehn-Hall,Kylene, Y1 - 2013/10/22/ PY - 2013/07/29/received PY - 2013/10/11/revised PY - 2013/10/15/accepted PY - 2013/10/29/entrez PY - 2013/10/29/pubmed PY - 2014/4/15/medline KW - Capsid KW - Ivermectin KW - Mifepristone KW - Nuclear export KW - Nuclear import KW - Venezuelan Equine Encephalitis Virus SP - 662 EP - 72 JF - Antiviral research JO - Antiviral Res VL - 100 IS - 3 N2 - Targeting host responses to invading viruses has been the focus of recent antiviral research. Venezuelan Equine Encephalitis Virus (VEEV) is able to modulate host transcription and block nuclear trafficking at least partially due to its capsid protein forming a complex with the host proteins importin α/β1 and CRM1. We hypothesized that disrupting the interaction of capsid with importin α/β1 or the interaction of capsid with CRM1 would alter capsid localization, thereby lowering viral titers in vitro. siRNA mediated knockdown of importin α, importin β1, and CRM1 altered capsid localization, confirming their role in modulating capsid trafficking. Mifepristone and ivermectin, inhibitors of importin α/β-mediated import, were able to reduce nuclear-associated capsid, while leptomycin B, a potent CRM1 inhibitor, confined capsid to the nucleus. In addition to altering the level and distribution of capsid, the three inhibitors were able to reduce viral titers in a relevant mammalian cell line with varying degrees of efficacy. The inhibitors were also able to reduce the cytopathic effects associated with VEEV infection, hinting that nuclear import inhibitors may be protecting cells from apoptosis in addition to disrupting the function of an essential viral protein. Our results confirm that VEEV uses host importins and exportins during part of its life cycle. Further, it suggests that temporarily targeting host proteins that are hijacked for use by viruses is a viable antiviral therapy. SN - 1872-9096 UR - https://www.unboundmedicine.com/medline/citation/24161512/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-3542(13)00294-5 DB - PRIME DP - Unbound Medicine ER -