Expression of cellular proteins Bcl-X(L), XIAP and Bax involved in apoptosis in cells infected with herpes simplex virus 1 and effect of pavine alkaloid (-)-thalimonine on virus-induced suppression of apoptosis.
The expression of three cellular proteins involved in the modulation of apoptosis, namely antiapoptotic Bcl-X(L) and XIAP and proapoptotic Bax, was investigated in cells infected with Herpes simplex virus 1 (HSV-1). To assess whether the regulation of apoptosis in virus-infected cells depends on strain specificity the wild-type (wt) strain Victoria and the mutant R-100 resistant to acyclovir (ACV) were used. In addition, the expression of Bcl-X(L), XIAP and Bax was studied in cells infected with HSV-1 and treated with pavine alkaloid (-)-thalimonine. Our previous work has demonstrated that (-)-thalimonine irreversibly inhibits the replication of wt HSV-1 in cultured cells. Our data showed that (-)-thalimonine down-regulates the expression of viral proteins U(L)17, VP11-12, VP22, VP24 and gamma1 34.5, and affects negatively the posttranslational processing of glycoproteins D (gD) and G (gG). As both gamma1 34.5 and glycoprotein D possess antiapoptotic activity, we investigated whether the antiviral effect of the alkaloid could also be due to its ability to suppress the antiapoptotic activity of the virus. Our results demonstrated that: (i) the virus induced overexpression of antiapoptotic proteins Bcl-X(L) and XIAP; (ii) (-)-thalimonine reduced their overexpression, and (iii) this effect was stronger with the acyclovir resistant mutant R-100 than with the wt virus. Taken together, these data suggest that: (i) the virus abolishes apoptosis by means of virus-induced up-regulation of cell-specific prosurvival proteins Bcl-X(L) and XIAP, and (ii) (-)-thalimonine, apart from affecting essential viral targets, inhibits the infectious progeny production via restoration of apoptosis during viral replication.
Angelova
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Laboratory of Virology, Faculty of Biology, University of Sofia, 8 Dragan Tzankov Blvd., 1421 Sofia, Bulgaria. assia6291@abv.bg
Tenev
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Varadinova
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D000212:Acyclovir / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D015536:Down-Regulation; D024882:Drug Resistance, Viral; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism*; D014779:Virus Replication; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000470:Alkaloids; D044182:Benzylisoquinolines; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C482652:3,4-methylenedeoxy-2,8,9-trimethoxypavinan; D000212:Acyclovir