Abstract
The life cycle of Kaposi’s sarcoma-associated herpesvirus (KSHV) consists of two phases, latent and lytic. The virus establishes latency as a strategy for avoiding host immune surveillance and fusing symbiotically with the host for lifetime persistent infection. However, latency can be disrupted and KSHV is reactivated for entry into the lytic replication. Viral lytic replication is crucial for efficient dissemination from its long-term reservoir to the sites of disease and for the spread of the virus to new hosts. The balance of these two phases in the KSHV life cycle is important for both the virus and the host and control of the switch between these two phases is extremely complex. Various environmental factors such as oxidative stress, hypoxia, and certain chemicals have been shown to switch KSHV from latency to lytic reactivation. Immunosuppression, unbalanced inflammatory cytokines, and other viral co-infections also lead to the reactivation of KSHV. This review article summarizes the current understanding of the initiation and regulation of KSHV reactivation and the mechanisms underlying the process of viral lytic replication. In particular, the central role of an immediate-early gene product RTA in KSHV reactivation has been extensively investigated. These studies revealed multiple layers of regulation in activation of RTA as well as the multifunctional roles of RTA in the lytic replication cascade. Epigenetic regulation is known as a critical layer of control for the switch of KSHV between latency and lytic replication. The viral non-coding RNA, PAN, was demonstrated to play a central role in the epigenetic regulation by serving as a guide RNA that brought chromatin remodeling enzymes to the promoters of RTA and other lytic genes. In addition, a novel dimension of regulation by microPeptides emerged and has been shown to regulate RTA expression at the protein level. Overall, extensive investigation of KSHV reactivation and lytic replication has revealed a sophisticated regulation network that controls the important events in KSHV life cycle.
Highlights
Studies of Kaposi’s sarcoma-associated herpesvirus (KSHV) in the last two decades have led to a great comprehension about reactivation and lytic replication of the virus including some common mechanisms shared by all herpesviruses and the unique features that contribute to the special life cycle of KSHV or gamma-herpesviruses as well as diseases associated with KSHV
The most compelling evidence for the role of T cell immunity in controlling KSHV reactivation came from Myoung and Ganem (2011) who showed that when mixed culture of human tonsillar B cells and activated T cells were exposed to KSHV, latent infection could be established in B cells with little spontaneous virus production
The ectopic expression of vSP-1 led to the increase of RTA abundance similar to that of T3.0 RNA. These results strongly suggested that T3.0 could regulate RTA expression through a microPeptide (Jaber and Yuan, 2013)
Summary
Pharmaceutical intervention of any of the three steps can break the chain of viral life cycle and serve as antiviral strategies for treatment of virally associated human diseases or cancers. Achieving this goal relies on a thorough comprehension of the processes in the viral life cycle and the underlying mechanisms. Studies of KSHV in the last two decades have led to a great comprehension about reactivation and lytic replication of the virus including some common mechanisms shared by all herpesviruses and the unique features that contribute to the special life cycle of KSHV or gamma-herpesviruses as well as diseases associated with KSHV. This review updates the current knowledge of the reactivation of latently infected KSHV and its lytic replication
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