Figure 5.

Contribution of STAT3 to gammaherpesvirus persistence. Infection of primary cells with gammaherpesviruses results in rapid activation of STAT3 (indicated in green). In the context of EBV infection, rapidly activated STAT3 blocks replication stress-induced cellular ATR-to-Chk1 signaling resulting in relaxation of the intra S phase cell cycle checkpoint; replication stress results from viral oncoprotein-driven cellular DNA replication. Relaxation of the intra S phase checkpoint ensures that infected cells do not undergo apoptosis or senescence in the early stages of infection, thereby promoting cell proliferation and establishment of viral latency. Latently-infected cells demonstrate high levels of STAT3 which contributes to cell survival and maintenance of latency. Furthermore, STAT3 transcriptionally activates cellular proteins PCBP2 and KAP1 that repress lytic genes, thus preventing loss of latency. The net effect of these STAT3-mediated activities is to promote gammaherpesvirus persistence.