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Nelfinavir impairs glycosylation of herpes simplex virus 1 envelope proteins and blocks virus maturation.

Gantt S, Gachelet E, Carlsson J, Barcy S, Casper C, Lagunoff M - Adv Virol (2015)

Bottom Line: NFV did not significantly affect the level of expression of late HSV-1 gene products.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

NFV inhibits production of infectious HSV-1 through a mechanism distinct from that of acyclovir and does not readily select for antiviral resistance in vitro. HSV-1 was passaged four times in HF in the presence of either 5 μM NFV or 1 μM acyclovir, the approximate IC50 of each drug. Virus passaged in acyclovir showed increased resistance to inhibition by acyclovir but was inhibited by NFV similarly to the control HSV-1 isolate. In contrast, passage in the presence of NFV did not result in a significant change in susceptibility to either drug. Shown are the results from three separate experiments.
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fig1: NFV inhibits production of infectious HSV-1 through a mechanism distinct from that of acyclovir and does not readily select for antiviral resistance in vitro. HSV-1 was passaged four times in HF in the presence of either 5 μM NFV or 1 μM acyclovir, the approximate IC50 of each drug. Virus passaged in acyclovir showed increased resistance to inhibition by acyclovir but was inhibited by NFV similarly to the control HSV-1 isolate. In contrast, passage in the presence of NFV did not result in a significant change in susceptibility to either drug. Shown are the results from three separate experiments.

Mentions: We passaged HSV-1 in the presence of NFV to determine if resistant mutants could be selected in an attempt to elucidate the mechanism of action of NFV on HHV production. As expected, [20] multistep passage under drug pressure was readily selected for high-level resistance to acyclovir (Figure 1). In contrast, no significant change in susceptibility to NFV was observed despite parallel passaging in the presence of NFV. Of note, the inhibitory activity of NFV was not different between acyclovir-resistant and wild type isolates, further suggesting a distinct antiviral mechanism.


Nelfinavir impairs glycosylation of herpes simplex virus 1 envelope proteins and blocks virus maturation.

Gantt S, Gachelet E, Carlsson J, Barcy S, Casper C, Lagunoff M - Adv Virol (2015)

NFV inhibits production of infectious HSV-1 through a mechanism distinct from that of acyclovir and does not readily select for antiviral resistance in vitro. HSV-1 was passaged four times in HF in the presence of either 5 μM NFV or 1 μM acyclovir, the approximate IC50 of each drug. Virus passaged in acyclovir showed increased resistance to inhibition by acyclovir but was inhibited by NFV similarly to the control HSV-1 isolate. In contrast, passage in the presence of NFV did not result in a significant change in susceptibility to either drug. Shown are the results from three separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4325974&req=5

fig1: NFV inhibits production of infectious HSV-1 through a mechanism distinct from that of acyclovir and does not readily select for antiviral resistance in vitro. HSV-1 was passaged four times in HF in the presence of either 5 μM NFV or 1 μM acyclovir, the approximate IC50 of each drug. Virus passaged in acyclovir showed increased resistance to inhibition by acyclovir but was inhibited by NFV similarly to the control HSV-1 isolate. In contrast, passage in the presence of NFV did not result in a significant change in susceptibility to either drug. Shown are the results from three separate experiments.
Mentions: We passaged HSV-1 in the presence of NFV to determine if resistant mutants could be selected in an attempt to elucidate the mechanism of action of NFV on HHV production. As expected, [20] multistep passage under drug pressure was readily selected for high-level resistance to acyclovir (Figure 1). In contrast, no significant change in susceptibility to NFV was observed despite parallel passaging in the presence of NFV. Of note, the inhibitory activity of NFV was not different between acyclovir-resistant and wild type isolates, further suggesting a distinct antiviral mechanism.

Bottom Line: NFV did not significantly affect the level of expression of late HSV-1 gene products.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus