Characterization of Two Divergent Lineages of Macaque Rhadinoviruses Related to Kaposi's Sarcoma-Associated Herpesvirus

Abstract

We have cloned and characterized the entire DNA polymerase gene and flanking regions from Kaposi's sarcoma-associated herpesvirus (KSHV) and two closely related macaque homologs of KSHV, retroperitoneal fibromatosis-associated herpesvirus-Macaca nemestrina (RFHVMn) and -Macaca mulatta (RFHVMm). We have also identified and partially characterized the corresponding genomic region of another KSHV-like herpesvirus, provisionally named "M. nemestrina rhadinovirus type 2 (MneRV-2)," with close similarity to rhesus rhadinovirus (RRV). A sequence comparison of these four macaque viruses and two KSHV-like gammaherpesviruses recently identified in African green monkeys, Chlorocebus rhadinovirus types 1 and 2 (ChRV-1 and ChRV-2) reveals the presence of two distinct lineages of KSHV-like rhadinoviruses in Old World primates. The first rhadinovirus lineage consists of KSHV and its closely related homologs RFHVMn, RFHVMm, and ChRV-1, while the second more distantly related lineage consists of RRV, MneRV-2, and ChRV-2. Our findings raise the possibility of the existence of another human KSHV-like herpesvirus belonging to the second rhadinovirus lineage.Kaposi's sarcoma-associated herpesvirus (KSHV) is postulated to be the infectious cause of Kaposi's sarcoma (KS) (for reviews, see references 5 and 19). Due to the strong similarities in sequence and gene organization with herpesvirus saimiri (HVS), the prototype of the gamma-2 (Rhadinovirus) genus of the gammaherpesvirus subfamily, KSHV has been classified as a human rhadinovirus (6, 13). We have previously identified DNA sequences related to KSHV in retroperitoneal fibromatosis (RF) lesions from two macaque species, the pig-tailed macaque (Macaca nemestrina) and the rhesus macaque (Macaca mulatta) (17). RF is a vascular fibroproliferative neoplasm with similarities to KS which was prevalent in the macaque colony in the Washington Regional Primate Research Center (WaRPRC) during the late 1970s and early 1980s (9, 10). The macaque KSHV-like sequences were identified using a novel consensus-degenerate hybrid oligonucleotide primer (CODE-HOP) PCR technique (16), which was employed to detect unknown herpesvirus DNA polymerase genes. Phylogenetic analysis of the available sequence data suggested that the DNA polymerase fragments were derived from macaque homologs of human KSHV, with a unique genotype present in each macaque species. These macaque homologs were designated RF-associated herpesvirus-M. nemestrina (RFHVMn) and -M. mulatta (RFHVMm). Subsequently, an additional simian homolog of KSHV was identified in an M. mulatta from the New England Regional Primate Research Center, and approximately 10 kb of the viral genome, including the DNA polymerase and flanking regions, was sequenced (8). Because of its sequence similarity to KSHV and HVS, this new homolog was designated rhesus rhadinovirus (RRV) isolate H26-95. Another isolate of RRV, RRV-17577, was identified in a simian immunodeficiency virus-infected rhesus macaque with a lymphoproliferative disorder at the Oregon Regional P...

A Novel γ2-Herpesvirus of the Rhadinovirus 2 Lineage in Chimpanzees

“…Rhadinoviruses, or ␥2-herpesviruses, have also been found in several animal species including New World monkeys (Herpesvirus ateles and Herpesvirus saïmiri) (Albrecht and Fleckenstein 1990;Albrecht 2000) and Old World monkeys (macaques, African green monkeys, and recently mandrills) (Desrosiers et al 1997;Rose et al 1997;Auerbach et al 2000;Greensill et al 2000b;Lacoste et al 2000c;Strand et al 2000). Comparison and phylogenetic analyses of available sequences support the existence of two distinct genogroups among the Old World monkey rhadinoviruses, called RV1 and RV2 for Rhadinovirus genogroups 1 and 2 (Bosch et al 1998;Greensill et al 2000b;Lacoste et al 2000c;Schultz et al 2000). KSHV belongs to the RV1 genogroup, whereas no human virus has yet been discovered in the RV2 group.…”

“…In instances in which particular animal species (macaques, Mandrills, and African green monkeys) have been thoroughly analyzed for the presence of ␥2-herpesviruses, at least two distinct viruses, each one belonging to a particular genogroup RV1 or RV2, have been identified (Desrosiers et al 1997;Rose et al 1997;Auerbach et al 2000;Greensill et al 2000b;Lacoste et al 2000c;Schultz et al 2000). To date, therefore, five distinct macaque ␥2-herpesviruses have been characterized, two in Macaca mulatta (RFHVMm and RRV/ MGVMm), two in Macaca nemestrina (RFHVMn and MneRV2/ MGVMn), one in Macaca fascicularis (MGVMf), and two in African green monkeys (ChRV1 and ChRV2) as well as in mandrills (MndRHV1 and MndRHV2).…”

Herpesvirus infections of laboratory macaques

“…Additional sequence analysis has clearly placed RFHV within the γR1 group of herpesviruses along with orthologous viruses such as KSHV and γR1 herpesviruses of chimpanzees, gorillas, and African green monkeys (Schultz et al, 2000;Rose et al, 2003;Westmoreland and Mansfield, 2008). Little is known about the pathogenesis of RFHV since virus has never been isolated or cultured so that detailed studies could be performed.…”

“…Rhadinoviruses have been grouped into two categories based upon phylogenetic relationships: γR1, which includes KSHV and retroperitoneal fibromatosis-associated herpesvirus (RFHV), and γR2, which includes rhesus rhadinovirus (RhRV), a more distantly-related macaque virus with no known human ortholog (Schultz et al, 2000).…”

Identification and functional characterization of a spliced rhesus rhadinovirus gene with homology to the K15 gene of Kaposi's sarcoma-associated herpesvirus

“…However, another macaque gamma-2 herpesvirus, retroperitoneal fibromatosis herpesvirus (RFHV), is even more closely related to KSHV (Rose et al, 1997(Rose et al, , 2003. On phylogenetic grounds, RRV is considered a representative of a second branch of Old World rhadinoviruses (RRV2), whilst the more closely related KSHV and RFHV are members of the first branch (RRV1) (Greensill et al, 2000;Lacoste et al, 2000;Schultz et al, 2000). In KSHV, the K15 gene, located between open reading frame (ORF) 75 and the terminal repeat (TR) region, consists of eight exons and is transcribed into several alternatively spliced transcripts during lytic replication (Choi et al, 2000;Glenn et al, 1999;Jenner et al, 2001;Nakamura et al, 2003;Poole et al, 1999).…”