Murid gammaherpesvirus 4 establishes latency and reactivates in a strain-dependent manner

Persistent infection with gammaherpesviruses, such as Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus may lead to development of various lymphomas and carcinomas in humans. Murid gammaherpesvirus 4 (MuHV-4, also known as MHV-68) is widely used as a model to study all aspects of gammaherpesvirus pathogenesis. Similar to human gammaherpesviruses, MuHV-4 is known for its variability, as evidenced by the existence of multiple strains/variants that differ from each other in primary sequence and some pathogenetic features. Detailed knowledge of the dependence of pathogenic properties on genome structure and sequence would help to better understand the complex host-pathogen interactions. The main aim of this study was to analyze how various strains/variants of MuHV-4, mainly MHV-72 and MHV-4556 induce latency and reactivation. In this study, we characterized the ability of MHV-72 and MHV-4556 to establish latency in spleen, lungs and thymus of immunocompetent mice after intranasal infection. Moreover, we described the potential of these strains to reactivate ex vivo using the method of tissue explantation and stimulation with inhibitor of histone deacetylases, trichostatin A. Our results clearly demonstrate that both MHV-72 and MHV-4556 exhibit a significant deficit in the establishment of deep latency in spleen. Moreover, MHV-72 has a reduced ability to establish latency in lungs as well as thymus. Regarding reactivation, we found that both MHV-72 and MHV-4556 have a significant deficit in ex vivo reactivation from latency in lungs as well as thymus in comparison to MHV-68. Moreover, MHV-72 also possessed a deficit in the ex vivo reactivation from spleen. In contrast, MHV-4556 was able to respond to the trichostatin A-mediated reactivation stimuli by increasing the DNA copy number but had a defect in the release from tissue during the early and deep latency in spleen. Our results contribute to molecular characterization of differences among the MuHV-4 strains in the ability to establish latency and reactivation and could also serve to better understanding of strain-dependent variances among human gammaherpesviruses.