It is now nearly three years since the seminal identificalesions and absent in uninvolved tissues. This search tion of the genome of a novel human herpesvirus in yielded two small fragments of DNA that showed clear Kaposi’s sarcoma (KS) specimens by Yuan Chang and homology to known herpesvirus sequences. From these colleagues (Chang et al., 1994). This discovery changed starting bits of DNA, the whole 170 kb genome has the face of KS research and ignited a passionate debate now been cloned in several laboratories; the complete about the role of this agent in the etiology of the tumor. sequence of one isolate has been published (Russo et Since then, progress in both laboratory and clinical inal., 1996) and that of a second is nearing completion vestigation has been swift, and both lines of work are(see Niepel et al., 1997). The sequence reveals KSHV converging on the view that the KS-associated herpesvito be a member of the herpes family’s lymphotropic rus (KSHV; also known by its formal taxonomic designasubgroup, whose best-known member is Epstein-Barr tion as human herpesvirus 8) plays a critical role in the virus (EBV). development of this neoplasm. Here we summarize the Not long after the first sighting of the genome, a B evidence linking virus and disease and consider some cell line (BCBL-1) was identified in which the KSHV geof the molecular mechanisms that might underly this nome is present in a latent state; treatment of these cells association. with phorbol esters induces dramatic lytic replication Backdrop: KS Epidemiology and Pathogenesis(Renne et al., 1996). This and subsequently identified KS is a peculiar neoplasm that differs from more com- similar lines allow high-level virus production, examinamon tumors in many respects. Histologically, the lesions tion of the activity of antiviral drugs, and experimental contain many different cell types, with the dominant access to the molecular biology of both latent and lytic cell being the so-called spindle cell, thought to be of infection. In addition, such lines have also served as endothelial origin. In addition, the tumors contain infil- sources of viral antigens for use in seroepidemiologic tratinginflammatorycellsaswellasaprofusionofhighly studies. Virus from these lines and from primary KS characteristic neovascular elements. In immunocompe- specimens can be transmitted to several other cultured tent hosts, KS is an indolent, largely local process, prop- cell lines, but this transmission is extremely inefficient erties suggestive of a low malignant potential. While(cf. Foreman et al., 1997). Passage to animal hosts has often more widespread in immunosuppressed hosts, in been similarly difficult: virus from BCBL-1 cells can be whom it can be disfiguring or even fatal, even partial transmitted to Rhesus macaques, but again infection restoration of immune competence can result in arrest occurs at an exceedingly low level and no disease is (and sometimes remission) of the disease—again distin- induced in the recipients. guishing it from more aggressive neoplasms. PCR-based studies on human tissues show that viral Much of what we know about the histogenesis of KS genomes are found in virtually all KS tumors, irrespective we owe to pioneering studies by Gallo and colleagues, of the stage of the lesion or the presence or absence who first developed reproducible systems for the culti- of HIV. KSHV genomes have also been strongly linked vation of spindle-like cells and established that these to several other proliferative lesions: certain AIDS-cells, while not fully transformed, elaborate a variety of related B cell lymphomas (these tumors were in fact the proinflammatory and …