Conquering the Host: Determinants of Pathogenesis Learned from Murine Gammaherpesvirus 68

Abstract

Gammaherpesviruses are an important class of oncogenic pathogens that are exquisitely evolved to their respective hosts. As such, the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) do not naturally infect nonhuman primates or rodents. There is a clear need to fully explore mechanisms of gammaherpesvirus pathogenesis, host control, and immune evasion in the host. A gammaherpesvirus pathogen isolated from murid rodents was first reported in 1980; 40 years later, murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68) infection of laboratory mice is a well-established pathogenesis system recognized for its utility in applying state-of-the-art approaches to investigate virus-host interactions ranging from the whole host to the individual cell. Here, we highlight recent advancements in our understanding of the processes by which MHV68 colonizes the host and drives disease. Lessons that inform KSHV and EBV pathogenesis and provide future avenues for novel interventions against infection and virus-associated cancers are emphasized.

A Polymorphism in the Epstein-Barr Virus EBER2 Noncoding RNA Drives In Vivo Expansion of Latently Infected B Cells

“…The oncogenic gammaherpesviruses, including human Epstein-Barr virus (EBV), human Kaposi’s sarcoma-associated herpesvirus (KSHV), and murine gammaherpesvirus 68 (MHV68, γHV68, MuHV-4), lead directly to the development of multiple types of malignancies, including B cell lymphomas ( 1 ). A central characteristic of gammaherpesviruses is the ability to establish lifelong latency in B cells, which is critical for tumorigenesis ( 1 ). However, the precise underlying mechanisms by which these viruses establish latency in vivo remain poorly understood.…”

“…However, the precise underlying mechanisms by which these viruses establish latency in vivo remain poorly understood. Gammaherpesviruses employ multiple means to promote latency establishment in B cells, including the expression of noncoding RNAs (ncRNAs) ( 1 , 2 ). Notably, although the EBV-encoded RNAs 1 and 2 (EBER1 and EBER2) are among the first viral ncRNAs ever identified ( 3 , 4 ), their specific in vivo functions remain largely unknown ( 2 , 5 ).…”

“…Gammaherpesviruses deploy multiple molecular strategies to modulate the balance between latency and reactivation and thereby establish lifelong infection in B cells ( 1 , 5 ). For example, terminal differentiation of infected B cells to plasma cells results in reactivation of EBV, KSHV, and MHV68 ( 20 – 22 ).…”

“…For example, terminal differentiation of infected B cells to plasma cells results in reactivation of EBV, KSHV, and MHV68 ( 20 – 22 ). Because B cells are a primary reservoir for both EBV and MHV68 latency ( 1 , 5 ) and plasma cells are a major source of reactivating virus in MHV68-infected mice ( 23 ), we determined whether B95-8 EBER2 promotes B cell latency through inhibition of plasma cell differentiation. To do so, we used multiparametric flow cytometry to analyze total and virus-positive B cells, germinal center (GC) B cells, and plasma cells in infected mice at 16 days postinfection (dpi) ( Fig.…”

Noncanonical circRNA biogenesis driven by alpha and gamma herpesviruses

“…KSHV seroprevalence varies by region and is highest in sub-Saharan Africa (>50%), the Mediterranean (20-30%), and among individuals living with HIV/AIDS in the U.S (~40%) (6,7). A closely related virus, murine gammaherpesvirus 68 (MHV68) or murid herpesvirus-4 (MuHV-4), has high genetic homology and serves as a tractable animal model for KSHV pathogenesis (8,9). Despite decades of study, a therapeutic agent capable of clearing these viruses or an effective vaccine is lacking.…”