Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication

Abstract

Kaposi’s sarcoma herpesvirus (KSHV) causes Kaposi’s sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication.

Kaposi's sarcoma herpesvirus-induced endothelial cell reprogramming supports viral persistence and contributes to Kaposi's sarcoma tumorigenesis

“…This KSHV-induced DDR appeared to be essential for latent gene expression and episome replication [66]. In addition, we and others have reported that in different KSHV-infection models the DDR is instigated upon lytic reactivation [67][68][69], thus suggesting that the virus replication induces a genomic stress that might represent a driving force in tumorigenesis or that DDR could provide a favorable host cell environment for efficient virus replication.…”

An easily transfectable cell line that produces an infectious reporter virus for routine and robust quantitation of Kaposi’s sarcoma-associated herpesvirus reactivation

“…In fact, this direct relationship between Rta’s relative potency and transfection efficiency was also observed in two other examples in which Rta was stably and uniformly expressed in human cells. (Balistreri et al, 2016; Myoung and Ganem, 2011; Nakamura et al, 2003). In B cells stably transfected with inducible Rta, lytic gene expression was more powerful and efficient upon direct induction of Rta, rather than treatment with HDACis (Nakamura et al, 2003).…”

“…In B cells stably transfected with inducible Rta, lytic gene expression was more powerful and efficient upon direct induction of Rta, rather than treatment with HDACis (Nakamura et al, 2003). Furthermore, human (SLK) cells stably infected with KSHV containing inducible Rta do not reactivate upon addition of HDACis alone (Balistreri et al, 2016). Instead, induction of Rta expression leads to low levels of reactivation which are enhanced by further addition of HDACis (Balistreri et al, 2016; Myoung and Ganem, 2011).…”

“…Furthermore, human (SLK) cells stably infected with KSHV containing inducible Rta do not reactivate upon addition of HDACis alone (Balistreri et al, 2016). Instead, induction of Rta expression leads to low levels of reactivation which are enhanced by further addition of HDACis (Balistreri et al, 2016; Myoung and Ganem, 2011). These results corroborate our findings in the Vero cells, suggesting Rta is a more potent inducer of viral reactivation than HDACis in both Vero and human cells.…”

p53 signaling modulation of cell cycle arrest and viral replication in porcine circovirus type 2 infection cells

“…For instance, Kaposi’s sarcoma herpesvirus (KSHV) activates host p53 signal and induces G2 phase arrest to promote the onset of virus replication [6]. Prototype foamy virus (PFV) promotes p53 level increase by knockdown of Pirh2 to contribute to the latency of PFV infection [7].…”