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Background: D-type simian retrovirus-2 (SRV-2) causes an AIDS-like immune deficiency syndrome (SAIDS) in various macaque species. SAIDS is often accompanied by retroperitoneal fibromatosis (RF), an aggressive fibroproliferative disorder reminiscent of Kaposi's sarcoma in patients with HIV-induced AIDS. In order to determine the association of SRV-2 subtypes with SAIDS-RF, and study the evolution and transmission of SRV-2 in captive macaque populations, we have molecularly characterized the env gene of a number of SRV-2 isolates from different macaque species with and without RF., Results: We sequenced the env gene from eighteen SRV-2 isolates and performed sequence comparisons and phylogenetic analyses. Our studies revealed the presence of six distinct subtypes of SRV-2, three of which were associated with SAIDS-RF cases. We found no association between SRV-2 subtypes and a particular macaque species. Little sequence variation was detected in SRV-2 isolates from the same individual, even after many years of infection, or from macaques housed together or related by descent from a common infected parent. Seventy-two amino acid changes were identified, most occurring in the larger gp70 surface protein subunit. In contrast to the lentiviruses, none of the amino acid variations involved potential N-linked glycosylation sites. Structural analysis of a domain within the gp22/gp20 transmembrane subunit that was 100% conserved between SRV-2 subtypes, revealed strong similarities to a disulfide-bonded loop that is crucial for virus-cell fusion and is found in retroviruses and filoviruses., Conclusion: Our study suggests that separate introductions of at least six parental SRV-2 subtypes into the captive macaque populations in the U.S. have occurred with subsequent horizontal transfer between macaque species and primate centers. No specific association of a single SRV-2 subtype with SAIDS-RF was seen. The minimal genetic variability of the env gene within a subtype over time suggests that a strong degree of adaptation to its primate host has occurred during evolution of the virus.

We previously identified retroperitoneal fibromatosis-associated herpesvirus (RFHV) as a simian homolog of Kaposi's sarcoma-associated herpesvirus (KSHV) in a fibroproliferative malignancy of macaques that has similarities to Kaposi's sarcoma. In this report, we cloned 4.3 kb of divergent locus B (DL-B) flanking the DNA polymerase gene from two variants of RFHV from different species of macaque with a consensus degenerate hybrid oligonucleotide primer approach. Within the DL-B region of RFHV, viral homologs of the cellular interleukin-6, dihydrofolate reductase, and thymidylate synthase genes were identified, along with a homolog of the gammaherpesvirus open reading frame (ORF) 10. In addition, a homolog of the KSHV ORF K3, the modulator of immune recognition-1, was identified. Our data show a close similarity in sequence conservation, gene content, and genomic structure between RFHV and KSHV which strongly supports the grouping of these viral species within the same RV-1 rhadinovirus lineage and the hypothesis that RFHV is the macaque homolog of KSHV.

Background: KSHV, Kaposi's sarcoma-associated herpesvirus, is a necessary cofactor for the development of Kaposi's sarcoma (KS). We have previously reported KSHV-related DNA sequences in retroperitoneal fibromatosis (RF) tissue from two species of macaque. The putative herpesvirus was called RFHV for RF-associated herpesvirus. These data suggested that KSHV is a human representative of a larger family of primate herpesviruses., Objective: To identify and characterize other members of a putative family of KSHV-related herpesviruses in macaques in order to obtain information on the evolutionary history of KSHV infection in humans., Study Design: Lymphoid tissue cells and blood leukocytes from rhesus-, cynomolgus- and pigtailed-macaques were tested for the presence of unknown herpesviruses using degenerate primer-driven PCR amplification. The sequences obtained were compared against known herpesvirus sequences., Results: We have identified new herpesvirus DNA sequences in each of the three macaque species. Sequence comparisons indicate that these new viruses are most related to each other and form a separate phylogenetic lineage within the gamma herpesviruses. Screening of PBMC from Indonesian-origin quarantine animals suggests that these viruses (MGV, macaque gamma virus) are species-specific, and highly prevalent in the wild. They are readily cultured in vivo, and share a common tissue tropism with the previously identified RFHV., Conclusions: MGV and RFHV represent two independent introductions of an ancestral gamma herpesvirus into macaque precursors.

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.

Budding endogenous retroviral particles were identified on the plasma membrane of a high percentage of neurotrophils in four widely varied pathological specimens.

Retroperitoneal fibromatosis-associated herpesvirus of rhesus macaques (RFHVMm) is a gammaherpesvirus closely related to human herpesvirus-8 (HHV-8), which is thought to be a necessary cofactor for the development of Kaposi's sarcoma (KS) in humans. Here, RFHVMm infection of rhesus macaques exposed to the D-type retrovirus simian retrovirus-2 (SRV-2) is described. Development of SRV-2 viraemia, infection with simian immunodeficiency virus or administration of cyclosporin A could result in persistent RFHVMm viraemia. From this, it is concluded that productive retrovirus infection or otherwise-induced immune suppression has the ability to activate this herpesvirus in vivo. Elevated levels of circulating interleukin-6, a cytokine that plays a central role in KS, were found in RFHVMm-viraemic animals. In viraemic animals, RFHVMm was found in tissues that are common sites for the development of AIDS-associated KS, especially the oral cavity. Together, these data suggest a common biology between RFHVMm infection of macaques and HHV-8 infection and pathogenesis in humans.

We describe a patient with hepatitis C related cryoglobulinemia and associated retroperitoneal fibrosis who developed massive proteinuria resulting from renal vein thrombosis.