Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of Delta U sub(S)3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1

• Published in: Journal of virology Vol. 80; no. 7; pp. 3341 - 3348
• Main Authors: Benetti, Luca, Roizman, Bernard
• Format: Journal Article
• Language: English
• Published: 01.04.2006
• Subjects: Herpes simplex virus 1
• ISSN: 0022-538X; 1098-5514

The product of the herpes simplex virus 1 (HSV-1) US3 gene is a multifunctional serine-threonine protein kinase that can block apoptosis induced by proapoptotic cellular proteins, exogenous agents, or replication-defective viruses. Earlier studies showed that the U sub(S)3 kinase activates and functionally overlaps cellular protein kinase A (PKA). In this study we examined the status of phosphatidylinositol 3-kinase [PI(3)K] and of its effector, protein kinase B/Akt (PKB/Akt), a component of a major pathway of mammalian antiapoptotic signaling systems. We report the following. (i) Infection of target cells with HSV-1 induces transient phosphorylation of serine 473 of PKB/Akt early in infection, with a mechanism that is dependent on PI(3)K. Inhibition of PI(3)K induced apoptosis in mock-infected or Delta U sub(S)3 mutant-virus-infected but not in wild-type-virus-infected cells and reduced the accumulation of specific viral gene products, including the U sub(S)3 protein kinase, but had a marginal effect on virus yields. (ii) At later times after infection, the total amounts of PKB/Akt decreased and phosphorylated PKB/Akt forms disappeared in a U sub(S)3-dependent and protein phosphatase 2A-independent manner. (iii) Activation of PKA by forskolin did not mediate significant dephosphorylation of PKB/Akt. Our results are consistent with the model that PKB/Akt is activated early in infection and acts to block apoptosis in infected cells prior to the accumulation of U sub(S)3 protein kinase and that it persists and continues to function as an antiapoptotic protein in the absence of U sub(S)3 but becomes redundant or even inimical once U sub(S)3 protein kinase accumulates in effective amounts.