title: Nelfinavir impairs glycosylation of herpes simplex virus 1 envelope proteins and blocks virus maturation.
abstract: Nelfinavir (NFV) is an HIV-1 aspartyl protease inhibitor that has numerous effects on human cells, which impart attractive antitumor properties. NFV has also been shown to have in vitro inhibitory activity against human herpesviruses (HHVs). Given the apparent absence of an aspartyl protease encoded by HHVs, we investigated the mechanism of action of NFV herpes simplex virus type 1 (HSV-1) in cultured cells. Selection of HSV-1 resistance to NFV was not achieved despite multiple passages under drug pressure. NFV did not significantly affect the level of expression of late HSV-1 gene products. Normal numbers of viral particles appeared to be produced in NFV-treated cells by electron microscopy but remain within the cytoplasm more often than controls. NFV did not inhibit the activity of the HSV-1 serine protease nor could its antiviral activity be attributed to inhibition of Akt phosphorylation. NFV was found to decrease glycosylation of viral glycoproteins B and C and resulted in aberrant subcellular localization, consistent with induction of endoplasmic reticulum stress and the unfolded protein response by NFV. These results demonstrate that NFV causes alterations in HSV-1 glycoprotein maturation and egress and likely acts on one or more host cell functions that are important for HHV replication.
authors.affiliation: Seattle Children's Research Institute, University of Washington, Seattle, WA 98101, USA ; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA ; Department of Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Gantt
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eliora
authors.initials: E
authors.lastname: Gachelet
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Carlsson
authors.affiliation: Seattle Children's Research Institute, University of Washington, Seattle, WA 98101, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Barcy
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA 98195, USA ; Department of Medicine, University of Washington, Seattle, WA 98195, USA ; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA ; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Casper
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lagunoff