Comparative pathobiology of Kaposi sarcoma-associated herpesvirus and related primate rhadinoviruses

Abstract

With the emergence of the AIDS epidemic over the last 2 decades and the more recent identification of Kaposi sarcoma-associated herpesvirus (KSHV, Human herpesvirus 8), the genera of rhadinoviruses have gained importance as a family of viruses with oncogenic potential. First recognized in New World primates more than 30 y ago, the rhadinoviruses Saimiriine herpesvirus 2 and Ateline herpesvirus 2 have well-described transforming capabilities. Recently several new species-specific rhadinoviruses of Old World primates have been described, including retroperitoneal fibromatosis herpesvirus and rhesus rhadinovirus (Cercopithecine herpesvirus 17). Molecular analysis of these viruses has elucidated several functionally conserved genes and properties shared with KSHV involved in cellular proliferation, transformation, and immune evasion that facilitate the oncogenic potential of these viruses. This review examines the comparative pathobiology of KSHV, discusses the role of macaque rhadinoviruses as models of human disease, and outlines the derivation of specific pathogen-free animals.

Figure 1.

Pathology of KSHV infection of humans. (A) Kaposi sarcoma (KS) and (B) multicentric Castleman disease (MCD) are associated with KSHV infection in immunocompromised and normal humans. KS is characterized by bundles of spindeloid cells forming fascicles and irregular channels containing erythrocytes. These spindeloid cells (C) may stain positively for latent nuclear antigen, (D) are vimentin-positive, and (E) often are negative for von Willebrand factor VII. MCD is a lymphoproliferative disorder characterized by generalized follicular lymphadenopathy with accumulation of plasma cells and proliferation of blood vessels within germinal centers (B). (F) Nucleic acid may be localized to the mantle region of affected follicles by means of in situ hybridization.

Figure 2.

Pathology of RFHV infection of macaques. (A) Retroperitoneal fibromatosis (RF) occurs in macaques coinfected with SRV2 and RFHV. The lesion shares some similarities with human KS, and virus may be localized to the proliferating spindeloid cells, (B) which form short bundles and fascicles but lack the vascular channels observed in KS. The lesion often arises at the root of the mesentery but may eventually surround and encase the gastrointestinal tract into a single mass (insert). An antiHHV8 LANA rat monoclonal antibody demonstrates characteristic nuclear punctuate staining in (C) an RF lesion and (D) a lymph node with angiofollicular lymphocytic hyperplasia.

Figure 3.

Pathology of RRV infection of macaques. (A) Experimental inoculation and natural infection initially is characterized by parafollicular lymphocytic hyperplasia, (B) accompanied by marked vascular hypertrophy and hyperplasia. (C) Florid follicular hyperplasia can occur after this phase, followed by (D) follicular dissolution or (E, F) follicles containing proliferative and hyalinized vessels. The lesions show similarities to plasma cell variant of MCD.