Model Systems of Gammaherpesvirus Infection, Immunity, and Disease.

Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are oncogenic human gammaherpesviruses (GHVs) associated with a broad spectrum of malignancies and chronic diseases. However, direct studies of these viruses in humans are limited by ethical constraints, technical challenges, and their strict species specificity. To overcome these barriers, researchers have developed surrogate models, with murine gammaherpesvirus 68 (MHV68) emerging as a tractable and widely utilized system. MHV68 shares key genetic and biological features with EBV and KSHV, providing critical insights into GHV pathogenesis, including viral latency, reactivation, immune evasion, and virus-host interactions. This review summarizes current cellular and animal models for GHV research, highlighting the advantages and limitations of MHV68 as a model for studying human GHVs. We explore mechanisms of viral gene function, immune modulation, and host responses, and discuss how these models have advanced our understanding of GHV-associated diseases. Improved model systems will be essential for guiding future experimental approaches and developing targeted therapies for GHV-driven malignancies and other related disorders.