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The Inhibition of PI3K-Akt Pathway Enhances Gamma-2 Herpesvirus Lytic Replication and Facilitates Reactivation from Latency

¹ UCLA;
² Institute of Biophysics, Chinese Academy of Sciences;
³ Memorial Sloan-Kettering Cancer Center

⁴ E-mail: rsun{at}mednet.ucla.edu

Cellular signaling pathways are critical in regulating the balance between latency and lytic replication of herpesviruses. Here we investigated the effect of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway on replication of two gamma-2 herpesviruses, murine gammaherpesvirus-68 (MHV-68) and human herpesvirus-8/Kaposi’s sarcoma associated herpesvirus (HHV-8/KSHV). We found that de novo infection of MHV-68 induced PI3K dependent Akt activation and the lytic replication of MHV-68 was enhanced by inhibiting the PI3K-Akt pathway with both chemical inhibitors and RNAi technology. Inhibiting the activity of Akt using Akt inhibitor VIII also facilitated the reactivation of KSHV from latency. Both lytic replication and latency depend on the activity of viral transactivator RTA and we further show that the activity of RTA is increased by reducing Akt1 expression. The data suggest that the PI3K-Akt pathway suppresses the activity of RTA and thereby contributes to the maintenance of viral latency and promote tumorigenesis.

Received 14 July 2009; accepted 28 October 2009.