Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle—latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target.
Highlights
Herpesviruses have been co-evolving with their animal hosts for millions of years
K15, a transmembrane protein expressed at low levels during latency, contributes to nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation by recruiting a complex composed of NF-κB-inducing kinase (NIK), IKKα, and IKKβ, which results in the serine 536 phosphorylation of p65 [33,34]. vFLIP forms a complex with cell adhesion molecule 1 (CADM1) and NEMO at the plasma membrane to promote IKK
replication and transcription activator (RTA) by binding its protein abundance regulatory signal (PARS) domain [71]. This domain is typically targeted by the cellular E3 ubiquitin ligase mouse double minute 2 homolog (MDM2), but competition by Nuclear receptor coactivator 2 (NCOA2) ensures the accumulation of RTA and activation of the lytic cycle [72]
Summary
Herpesviruses have been co-evolving with their animal hosts for millions of years. The life cycle of these viruses represents a compromise with the host immune system, forged by selective pressures to produce viral progeny while minimizing damage to the host that would compromise viral fitness. In response to external factors, latency can be disrupted by a bout of lytic reactivation, which triggers expression of the entire viral genome, replication of viral episomes via a rolling-circle mechanism, and production of infectious virions [2]. Since this phase of the viral life cycle results in the expression of many viral proteins, thereby exposing the virus to detection by the host immune system, entry into the lytic cycle is tightly controlled by a wide variety of mechanisms [3].
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