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.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
Li
L
Peng
Ting-Ting
TT
Wu
Jason H
JH
Tchieu
Jun
J
Feng
Helen J
HJ
Brown
Jiaying
J
Feng
Xudong
X
Li
Jing
J
Qi
Hongyu
H
Deng
Igor
I
Vivanco
Ingo K
IK
Mellinghoff
Christina
C
Jamieson
Ren
R
Sun
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