Callitrichine herpesvirus 3 in the common marmoset is a model of Epstein-Barr virus infection and associated lymphoma

Herpesviruses, such as Epstein-Barr virus (EBV), are thought to potentially play a significant role in multiple disease processes, including neoplasia, multiple sclerosis (MS), and more recently, Alzheimer's disease (AD). Animal models remain vital tools for understanding these diseases and developing therapeutics. Callitrichine herpesvirus 3 (CalHV-3) was identified in the early 2000s in the common marmoset (Callithrix jacchus). Although phylogenetically related to human EBV, the biological similarities between CalHV-3 and EBV have not been thoroughly characterized. Over 450 marmosets from five biomedical research colonies in the United States were screened for CalHV-3 using droplet digital PCR (ddPCR). Peripheral blood mononuclear cells (PBMCs) were magnetically separated to determine viral loads in B-cell selected and B-cell depleted populations. A CalHV-3 infected cell line was reactivated to determine gene expression profiles using quantitative-Reverse Transcription PCR (q-RT-PCR). Archived cases of lymphoma in the marmoset were immunophenotyped by immunohistochemistry (IHC). In the neoplastic tissue, CalHV-3 viral loads were measured by ddPCR, and viral transcripts were visualized using RNAscope. The prevalence of CalHV-3 in these research colonies ranged from 19-63%. The virus was detected longitudinally in PBMCs and saliva. Infected marmosets had CalHV-3 viral loads enriched in B-cells. All cases of B-cell lymphoma in the marmoset were positive for CalHV-3 DNA, with transcripts of EBV latent and lytic gene homologs detected in neoplastic tissue. Like EBV, CalHV-3 is characterized by persistent infection, shedding in saliva, B-cell tropism, latent and lytic gene expression profiles, and lymphomagenesis in a subset of infected animals. These results further suggest that CalHV-3 in the common marmoset may serve as a translational model of EBV infection and associated diseases.