A Novel Epstein-Barr Virus-Like Virus, HVMNE, in aMacaca Nemestrina With Mycosis Fungoides

Abstract

Epstein-Barr virus (EBV) infection of humans has been associated with the development of lymphoid malignancies mainly of B-cell lineage, although occasionally T-cell lymphomas have been reported. We describe here the characterization of a novel EBV-like virus (HVMNE) isolated from a simian T-cell lymphotropic virus type I/II (STLV-I/II) seronegative pigtailed macaque (Macaca nemestrina) with a cutaneous T-cell lymphoma. Immunohistochemistry studies on the skin lesions demonstrated that the infiltrating cells were of the CD3+/CD8+ phenotype. Two primary transformed CD8+ T-cell lines were obtained from cultures of peripheral blood mononuclear cells (PBMC) and skin, and, with time, both cell lines became interleukin-2–independent and acquired the constitutive activation of STAT proteins. Polymerase chain reaction analysis of the DNA from the cell lines and tissues from the lymphomatous animal demonstrated the presence of a 536-bp DNA fragment that was 90% identical to EBV polymerase gene sequences, whereas the same DNA was consistently negative for STLV-I/II sequences. Electron microscopy performed on both cell lines, after sodium butyrate treatment, showed the presence of a herpes-like virus that was designated HVMNE according to the existing nomenclature. In situ hybridization studies using EBV Epstein-Barr viral-encoded RNA probes showed viral RNA expression in both CD8+ T-cell lines as well as in the infiltrating CD8+ T cells of skin-tissue biopsies. Phylogenetic analysis of a 465-bp fragment from the polymerase gene of HVMNE placed this virus within theLymphocryptovirus genus and demonstrated that HVMNEis a distinct virus, clearly related to human EBV and other EBV-like herpesviruses found in nonhuman primates.

Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis

“…The same DNA fragment was found also in two CD8+ T-cell lines established from this tumor. Sequencing analysis of this fragment revealed 90% sequence identity with EBV DNA polymerase, and phylogenetic analysis indicated a distinct virus (HV MNE ) of the LCV genus [84]. Furthermore, herpesvirus-like particles were demonstrated by electron microscopy in the two T-cell lines [84].…”

“…Sequencing analysis of this fragment revealed 90% sequence identity with EBV DNA polymerase, and phylogenetic analysis indicated a distinct virus (HV MNE ) of the LCV genus [84]. Furthermore, herpesvirus-like particles were demonstrated by electron microscopy in the two T-cell lines [84]. Subsequent studies showed that HV MNE transformed rabbit T cells and induced T-cell lymphoma in rabbits [85].…”

“…LCVs are mostly B-lymphotropic and cause LPD/lymphoma of B-cell origin, but identification of an exceptional T-cell tropic species of LCV has been reported [84]. A viral DNA fragment was identified in the lesion of cutaneous T-cell lymphoma in a pig-tailed macaque (Macaca nemestrina).…”

Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV

“…Experimental infection of macaques with RLCV and RRV have been used as models for AIDS-associated malignancies caused by gammaherpesviruses [ 9 – 13 ]. In addition, a related virus isolated from pig tailed macaques with lymphoma was shown to cause lymphoma in rabbits[ 14 , 15 ]. However, the role of naturally occurring gammaherpesvirus infections in macaques subsequently infected experimentally with SIV/SHIV and their role in malignancies has not been extensively studied.…”

Characterization of an Epstein–Barr virus-related gammaherpesvirus from common marmoset (Callithrix jacchus)

“…EBV-like viruses in closely related primates have been recognized for over 25 years including Herpesvirus gorilla ( Pongine herpesvirus 3 ) (Neubauer et al ., 1979 ), Herpesvirus pan ( Pongine herpesvirus 1 ) (Gerber et al , 1976 ; Landon et al ., 1968 ), Herpesvirus pongo ( Pongine herpesvirus 2 ) (Rabin et al , 1978 ) and Herpesvirus papio ( Cercopithecine herpesvirus 12 ) (Falk et al ., 1976 , 1977 ), all belonging to the lymphocryptovirus subgroup of the gammaherpesvirus subfamily. More recently, lymphocryptoviruses have been identified in lymphoid tumours of several macaque species including cynomolgus macaque ( Macaca fascicularis ) (Hayashi et al ., 1995 , 1999 ; Li et al ., 1994 ), stump-tailed macaque ( Macaca arctoides ) (Wutzler et al ., 1995 ), pig-tailed macaque ( Macaca nemestrina ) (Rivadeneira et al ., 1999 ) and rhesus macaque ( Macaca mulatta ) (Moghaddam et al ., 1997 , 1998 ; Rangan et al ., 1986 ; Rivailler et al ., 2002 ). Various models for EBV-related lymphoid disease and infection have been developed from these findings.…”