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Abstract
Herpesviruses establish a chronic infection in the host characterized by intervals of lytic replication, quiescent latency, and reactivation from latency. Murine gammaherpesvirus 68 (MHV68) naturally infects small rodents and has genetic and biologic parallels with the human gammaherpesviruses (gHVs), Kaposi’s sarcoma-associated herpesvirus and Epstein–Barr virus. The murine gammaherpesvirus model pathogen system provides a platform to apply cutting-edge approaches to dissect the interplay of gammaherpesvirus and host determinants that enable colonization of the host, and that shape the latent or lytic fate of an infected cell. This knowledge is critical for the development of novel therapeutic interventions against the oncogenic gHVs. The nuclear factor kappa B (NF-κB) signaling pathway is well-known for its role in the promotion of inflammation and many aspects of B cell biology. Here, we review key aspects of the virus lifecycle in the host, with an emphasis on the route that the virus takes to gain access to the B cell latency reservoir. We highlight how the murine gammaherpesvirus requires components of the NF-κB signaling pathway to promote replication, latency establishment, and maintenance of latency. These studies emphasize the complexity of gammaherpesvirus interactions with NF-κB signaling components that direct innate and adaptive immune responses of the host. Importantly, multiple facets of NF-κB signaling have been identified that might be targeted to reduce the burden of gammaherpesvirus-associated diseases.
Highlights
Latency is defined by extremely restricted viral gene expression, the maintenance of the viral genome as a circular non-integrated episome tethered to the cellular genome (Yates and Guan, 1991; Ballestas et al, 1999; Lee et al, 1999; Collins et al, 2002; Habison et al, 2012), and the ability to switch from latent infection to productive virus infection, a process known as reactivation
Epstein–Barr virus (EBV) infects over 95% of adult humans, while Kaposi’s sarcoma-associated herpesvirus (KSHV) infection varies by geographical location and HIV infection status
Murine gammaherpesvirus 68 (MHV68) is classified as a Rhadinovirus along with KSHV and herpesvirus saimiri (HVS, saimiriine herpesvirus 2)
Summary
The gammaherpesviruses (gHVs) represent an ancient and highly successful family of viruses that coevolved with their hosts over the course of 60–80 million years (Davison, 2002). Herpesvirus virions are surrounded by a lipid envelope that contains numerous glycoproteins that mediate entry into the cell. A hallmark of herpesvirus infection, including that of the gHVs, is the ability to switch between two distinct phases: lytic infection and latency. Latency is defined by extremely restricted viral gene expression, the maintenance of the viral genome as a circular non-integrated episome tethered to the cellular genome (Yates and Guan, 1991; Ballestas et al, 1999; Lee et al, 1999; Collins et al, 2002; Habison et al, 2012), and the ability to switch from latent infection to productive virus infection, a process known as reactivation. The predominant cellular reservoir of latency is lymphocytes; the human gHVs target the mature B cell compartment (Ambroziak et al, 1995; Babcock et al, 1998; Hassman et al, 2011)
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