The idea that KS might have an infectious cause is an old one that derives from several sources. First, the complex histology of the lesion, its multicentric nature, the indolent character of the disease (in its classical form), its occasional spontaneous regression and the evidence for oligo-or poly-clonality (see below) all suggest that KS is not a traditional malignancy. As early as the 1970’s speculation abounded that the African form was linked to cytomegalovirus (CMV) infection^1-3a notion that was ultimately disproven. Suspicions of a viral etiology were again aroused in the AIDS era, since HIV-positive subjects appeared to be at enormous risk for developing this once-rare condition⁴. Although it was natural to wonder whether HIV itself might be the proximate cause of KS, this notion was complicated by the finding that KS spindle cells do not harbor HIV DNA. This led to suggestions that HIV-infected cells might provide factors in trans that stimulate KS spindle cells to grow, a notion for which there is considerable in vitro evidence (see below). But epidemiological studies of AIDS-KS in the US and Europe soon established the decisive fact that even among HIV-positive subjects there were wide differences in KS risk⁴. Male homosexuals with HIV are 20-30 times more likely to develop KS than HIV-infected hemophiliacs or IV drug users and KS is rarer still in children with vertically-acquired HIV. These seminal observations suggested that a second, possibly sexually transmitted, factor was a critical determinant of KS risk and precipitated a search for potential pathogens in KS tissue.