Kaposi's sarcoma-associated herpesvirus latent gene vFLIP inhibits viral lytic replication through NF-kappaB-mediated suppression of the AP-1 pathway: a novel mechanism of virus control of latency.
Kaposi's sarcoma-associated herpesvirus (KSHV) latency is central to the evasion of host immune surveillances and induction of KSHV-related malignancies. The mechanism of KSHV latency remains unclear. Here, we show that the KSHV latent gene vFLIP promotes viral latency by inhibiting viral lytic replication. vFLIP suppresses the AP-1 pathway, which is essential for KSHV lytic replication, by activating the NF-kappaB pathway. Thus, by manipulating two convergent cellular pathways, vFLIP regulates both cell survival and KSHV lytic replication to promote viral latency. These results also indicate that the effect of the NF-kappaB pathway on KSHV replication is determined by the status of the AP-1 pathway and hence provide a mechanistic explanation for the contradictory role of the NF-kappaB pathway in KSHV replication. Since the NF-kappaB pathway is commonly activated during infection of gammaherpesviruses, these findings might have general implications for the control of gammaherpesviral latency.
Ye
Feng-Chun
FC
Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Zhou
Fu-Chun
FC
Xie
Jian-Ping
JP
Kang
Tao
T
Greene
Whitney
W
Kuhne
Kurt
K
Lei
Xiu-Fen
XF
Li
Qui-Hua
QH
Gao
Shou-Jiang
SJ
D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D017735:Virus Latency / Q000235:genetics*; D014779:Virus Replication
D017874:Immediate-Early Proteins; D016328:NF-kappa B; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8