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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

Decreased Akt activation does not account for the ability of NFV to inhibit HSV-1 viral replication. HSV-1 infection of Vero cells resulted in an increase in levels of phosphorylated (p)-Akt at 2 hours compared to uninfected cells. Although the Akt inhibitor LY294002 could completely suppress Akt phosphorylation in HSV-1 infected cells, NFV did not substantially reduce the levels of p-Akt even at drugs concentrations that potently block virus production.
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fig3: Decreased Akt activation does not account for the ability of NFV to inhibit HSV-1 viral replication. HSV-1 infection of Vero cells resulted in an increase in levels of phosphorylated (p)-Akt at 2 hours compared to uninfected cells. Although the Akt inhibitor LY294002 could completely suppress Akt phosphorylation in HSV-1 infected cells, NFV did not substantially reduce the levels of p-Akt even at drugs concentrations that potently block virus production.

Mentions: One of the prominent effects of NFV on human cells that has been described is inhibition of the Akt signaling pathway by reducing the phosphorylation of Akt by phosphatidylinositol-3 kinase [21–23]. HSV-1 infection results in an increase in the level of Akt phosphorylation (Figure 3), as has been previously described [24]. The Akt inhibitor LY294002 completely suppressed Akt phosphorylation in HSV-1 infected cells, but NFV did not reduce the levels of phosphorylated Akt even at drug concentrations that potently block virus production (Figure 3). Furthermore, LY294002 treatment of HSV-1 infected HF cells did not reduce the production of infectious virus by plaque assay (not shown), consistent with published data [24]. Therefore, it is unlikely that the documented inhibition of NFV on AKT activation plays a role in the drug's inhibition of HSV-1.


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)

Decreased Akt activation does not account for the ability of NFV to inhibit HSV-1 viral replication. HSV-1 infection of Vero cells resulted in an increase in levels of phosphorylated (p)-Akt at 2 hours compared to uninfected cells. Although the Akt inhibitor LY294002 could completely suppress Akt phosphorylation in HSV-1 infected cells, NFV did not substantially reduce the levels of p-Akt even at drugs concentrations that potently block virus production.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Decreased Akt activation does not account for the ability of NFV to inhibit HSV-1 viral replication. HSV-1 infection of Vero cells resulted in an increase in levels of phosphorylated (p)-Akt at 2 hours compared to uninfected cells. Although the Akt inhibitor LY294002 could completely suppress Akt phosphorylation in HSV-1 infected cells, NFV did not substantially reduce the levels of p-Akt even at drugs concentrations that potently block virus production.
Mentions: One of the prominent effects of NFV on human cells that has been described is inhibition of the Akt signaling pathway by reducing the phosphorylation of Akt by phosphatidylinositol-3 kinase [21–23]. HSV-1 infection results in an increase in the level of Akt phosphorylation (Figure 3), as has been previously described [24]. The Akt inhibitor LY294002 completely suppressed Akt phosphorylation in HSV-1 infected cells, but NFV did not reduce the levels of phosphorylated Akt even at drug concentrations that potently block virus production (Figure 3). Furthermore, LY294002 treatment of HSV-1 infected HF cells did not reduce the production of infectious virus by plaque assay (not shown), consistent with published data [24]. Therefore, it is unlikely that the documented inhibition of NFV on AKT activation plays a role in the drug's inhibition of HSV-1.

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