Comparative Pathobiology of Kaposi Sarcoma-associated Herpesvirus and Related Primate Rhadinoviruses

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.Abbreviations: CCL, cellular chemokine ligand; IRF, interferon regulatory factors; KSHV, Kaposi sarcoma-associated herpesvirus; LANA, latent nuclear antigen; MCD, multicentric Castleman disease; MCP1, monocyte chemotactic protein 1; miRNA, microRNA; ORF, open reading frame; PEL, primary effusion lymphoma; RFHV, retroperitoneal fibromatosis herpesvirus; RVV, rhesus rhadinovirus; SaHV2, Saimiriine herpesvirus 2; SPF, specific pathogen-free; SRV2, simian retrovirus type 2; THBS1, thrombospondinMembers of the herpesviridae are enveloped DNA viral agents that can infect a variety of host species, resulting in lifelong infection. The family is divided into Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae, according to biologic behavior and phylogenetic relationship. As a group, synthesis of viral DNA occurs in the nucleus, and production of infectious virions is associated with destruction of the cell. Herpesviruses have large complex genomes and often have acquired host genes that allow these viruses to modulate and persist in the face of host immune responses.^25,71 This condition (termed ‘latency’) is characteristic of all herpesviral infections of the natural host. Although most members of the herpesviridae are of relatively low virulence in their respective hosts, some lack strict host specificity, and cross-species transmission to an inadvertent host can be associated with severe and fatal disease.The gammaherpesvirinae subfamily is characterized by in vitro and in vivo infection of lymphoblastoid cells and is further divided into the lymphocryptovirus (γ1 herpesviruses) and rhadinovirus (γ2 herpesviruses) genera. Rhadinoviruses have taken on increased importance with the identification of the novel Kaposi sarcoma-associated herpesvirus (KSHV, Human herpesvirus 8) in association with Kaposi sarcoma, an inflammatory and neoplastic condition seen in many HIV-infected patients with AIDS.^20,22 Until the recognition of KSHV more than a decade ago, rhadinovirus infection of primates was thought to be restricted to the New World primate lineages, but subsequent investigation revealed a number of novel species-specific viruses in a variety of Old World primates (28 As discussed later, based largely on phylogenetic analysis, it is now believed that the rhadinoviruses are subdivided into 2 distinct groupings (rhadinovirus [RV] 1 and 2).⁷⁷ This review will examine 2 recently recognized rhadinoviruses of macaques (retroperitoneal fibromatosis virus [RFHV] and rhesus rhadinovirus [RRV, Cercopethecine herpesvirus 17]), focusing on their comparative pathobiology with KSHV, their impact on naturally occurring disease entities, and their roles as animal models of human disease.

Table 1.

Nomenclature of primate rhadinoviruses (RV)

Group	Abbreviation	Official designationa	Alternative designation	Host	Virus isolated	Genomic sequence available
RV1
	HHV8	Human herpesvirus 8	KSHV	Homo sapiens	yes	yes
	RV1mmu	not available	RFHVmmu	Macaca mulatta	no	no
	RV1mne	not available	RFHVmne	Macaca nemestrina	no	no
	RV1pan	not available	PtRV1a and	Pan troglodytes	no	no
			PtRV1b
	RV1gor	not available	GorRV1	Gorilla gorilla	no	no
	RV1agm	not available	ChRV1	Chlorocebus aethiops	no	no
RV2
	HVS	Saimirine herpesvirus 2 (SaHV2)	none	S. sciureus	yes	yes
	HVA	Ateline herpesvirus 2 (AtHV2)	none	Ateles geoffroyi	yes	yes
	RV2mmu	Cercopethecine herpesvirus 17 (CeHV17)	RRV	Macaca mulatta	yes	yes
	RV2mne	not available	PRV	Macaca nemestrina	yes	no
	RV2pan	not available	PtRV2	Pan troglodytes	no	no
	RV2agm	not available	ChRV2	Chlorocebus aethiops	no	no
	RV2pan	not available	PapRV2	Pan anubis	no	no

Open in a separate window^aFrom the International Committee on Taxonomy of Viruses.