Comparative pathobiology of macaque lymphocryptoviruses

Abstract

Lymphocryptoviruses (LCVs) have been identified as naturally occurring infections of both Old and New World nonhuman primates. These viruses are closely related to Epstein-Barr virus (EBV, Human herpesvirus 4) and share similar genomic organization and biological properties. Nonhuman primate LCVs have the ability to immortalize host cells and express a similar complement of viral lytic and latent genes as those found in EBV. Recent evidence indicates that nonhuman primate LCVs can immortalize B cells from genetically related species, suggesting a close evolutionary relationship between these viruses and their respective hosts. Early work with EBV in tamarins and owl monkeys revealed that cross species transmission of lymphocryptoviruses from the natural to inadvertent host may be associated with oncogenesis and the development of malignant lymphoma. Moreover, simian LCVs have the ability to induce malignant lymphomas in immunodeficient hosts and have been associated with posttransplantation lymphoproliferative disease in cynomolgus macaques undergoing solid organ transplantation. This review will focus on the comparative pathobiology of lymphocryptoviral infection and discuss the derivation of specific pathogen-free animals.

Figure 1.

Lymphocryptovirus and oral leukoplakia in simian AIDS. Oral leukoplakia has been diagnosed as a common opportunistic infection during the course of human and simian AIDS. (A) Raised plaques occur most frequently on the oral and esophageal mucosa and (B) consist of epithelial cells undergoing ballooning degeneration. (C) Well-formed intranuclear inclusion are evident, and (D) viral proteins, such as BZLF1, and viral nucleic acid can be demonstrated in infected cells.

Figure 2.

Lymphocryptovirus and non-Hodgkin lymphoma (NHL) in simian AIDS. NHL has been diagnosed in rhesus and cynomolgus macaques during the course of progressive immunodeficiency and is the most common malignancy in simian AIDS. These lymphomas may be nodal or extranodal (A, skeletal muscle) and frequently contain viral latent antigen (B, EBNA2). (C) Infiltrates consist of neoplastic CD20⁺ B cells and (D) express a variety of cellular oncogenes, such as bcl2.

Figure 3.

Lymphocryptovirus (LCV) and posttransplantation lymphoproliferative disease (PTLD). LCV has been associated with lymphoproliferative disorders in cynomolgus macaques after solid organ transplantation in a process analogous to PTLD in human patients. These lymphomas are often extranodal and may be found in a variety of organs, such as the liver (A, B), and express LCV latent antigens, such as EBNA2 (C).