Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis

Abstract

Epstein–Barr virus (EBV) is involved in the pathogenesis of various lymphomas and carcinomas, whereas Kaposi’s sarcoma-associated herpesvirus (KSHV) participates in the pathogenesis of endothelial sarcoma and lymphomas. EBV and KSHV are responsible for 120,000 and 44,000 annual new cases of cancer, respectively. Despite this clinical importance, no chemotherapies or vaccines have been developed for virus-specific treatment and prevention of these viruses. Humans are the only natural host for both EBV and KSHV, and only a limited species of laboratory animals are susceptible to their experimental infection; this strict host tropism has hampered the development of their animal models and thereby impeded the study of therapeutic and prophylactic strategies. To overcome this difficulty, three main approaches have been used to develop animal models for human gammaherpesvirus infections. The first is experimental infection of laboratory animals with EBV or KSHV. New-world non-human primates (NHPs) and rabbits have been mainly used in this approach. The second is experimental infection of laboratory animals with their own inherent gammaherpesviruses. NHPs and mice have been mainly used here. The third, a recent trend, employs experimental infection of EBV or KSHV or both to immunodeficient mice reconstituted with human immune system components (humanized mice). This review will discuss how these three approaches have been used to reproduce human clinical conditions associated with gammaherpesviruses and to analyze the mechanisms of their pathogenesis.

Epstein–Barr Virus+ B Cells in Breast Cancer Immune Response: A Case Report

“…The development of EBV+ lymphocytic neoplasms in PDX derived from breast cancer had also been previously described ( 10 ). This can be explained by the lack of a mature immune system in the PDX models, which are NSG mice, and the evidence that EBV infection more frequently leads to lymphoproliferative disorders in immunosuppressive contexts ( 20 , 69 , 70 ). We are not aware that these XABCLs have been used before as a model to investigate the role of tumor-infiltrating EBV+ B cells.…”

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

“…Because of its restricted species tropism, studying KSHV infection in vivo is not straightforward. There are mainly three ways of how KSHV infection can be studied in vivo (nicely reviewed in [177]): the first is to infect non-human primates like common marmosets with KSHV [178]. The second approach involves the use of KSHV related viruses, like murine herpesvirus 68 (MHV-68), rhesus rhadinovirus (RRV) [179] or herpesvirus saimiri (HVS) [180].…”

Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

“…In addition, experimental infection of primates with primate GHVs leads to the colonization of cells, immune response, and pathologies that parallel their human GHV counterparts [ 3 , 139 , 140 ]. Primate pathogens systems are important to refine knowledge of virus–host interactions at the organismal level and they can provide important pre-clinical evaluation of novel interventions [ 141 ]. Cost and ethical considerations, in addition to limitations such as genetically tractable animals, are a barrier to widespread adoption of pathogenesis studies in primates.…”

“…Approaches to test how factors encoded by the human GHV influence the infected B cells include gain of function experiments that introduce human GHV genes into MHV68 or genetically complement MHV68 mutants [ 145 , 146 , 147 , 148 , 149 ]. The analysis of EBV and KSHV in humanized mice is an exciting advancement that enables some degree of B cell interactions with cognate T cells [ 141 , 150 , 151 ].…”