HUMAN HERPESVIRUS 8 (HHV-8) ENCODES A HOMOLOGUE OF CELLULAR CYCLIN D2 THAT IS EXPRESSED IN KAPOSI'S SARCOMA (KS) LESIONS AND POTENTIAL KS PROGENITORS.

Abstract

Background: A novel human herpesvirus, HHV-8, is now implicated in the pathogenesis of all forms of KS, primary effusion (body-cavity based) lymphoma (PEL), and multicentric Castleman's disease. Consequently, the identification and characterization of those HHV-8 gene products expressed in these proliferative processes may clarify a role for HHV-8 in these disease states. Methods: To examine the role of HHV-8 in KS pathogenesis, HHV-8 containing genomic and cDNA libraries were prepared from a PEL. HHV-8 specific genomic clones were used to screen the PEL cDNA library. Analyses of viral transcripts corresponding to a representative viral cDNA was performed using reverse-transcriptase polymerase chain reaction (RT-PCR). Northern Blot analyses, and in situ hybridization with sense and antisense RNA probes. Results: DNA sequence analysis of one of the HHV-8 cDNA clones isolated encodes for a 28.9 kDa protein with homology to human and mouse cellular cyclin D2, and the cyclin homologue of Herpesvirus saimiri. RT-PCR analyses show HHV-8 cyclin transcripts in PEL and KS biopsies, cultured PEL, early passage KS cells, and in the circulating KS-like spindle cells. In situ hybridization show that transcripts for the viral cyclin are found in the majority of spindle cells in KS lesions. Transcripts for the latency-associated viral gene. T0.7 share similar expression patterns in KS lesions. Conclusion: In this report, we describe the isolation and characterization of an HHV-8 homologue of cellular cyclin D2. In situ hybridization studies suggest that the viral cyclin may play a role in maintaining viral latency in KS cells and possibly be responsible for the high proliferative rate of the sppindle cells in KS lesions. Moreover, expression of HHV-8 cyclin in the circulating KS-like spindle cells (Blood 84(8):2711,1994) may explain why these cells are increased in the circulation of patients with KS and those at high risk to develop KS.