Inhibition of the phosphatidylinositol 3-kinase-Akt pathway enhances gamma-2 herpesvirus lytic replication and facilitates reactivation from latency.
Cellular signalling 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 RNA interference 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 promotes tumorigenesis.
Peng
Li
L
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
Wu
Ting-Ting
TT
Tchieu
Jason H
JH
Feng
Jun
J
Brown
Helen J
HJ
Feng
Jiaying
J
Li
Xudong
X
Qi
Jing
J
Deng
Hongyu
H
Vivanco
Igor
I
Mellinghoff
Ingo K
IK
Jamieson
Christina
C
Sun
Ren
R
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D018142:Gammaherpesvirinae / Q000235:genetics / Q000502:physiology*; D006566:Herpesviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D015534:Trans-Activators; D014764:Viral Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt