Molecular virology of Kaposi's sarcoma-associated herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV), the most recently discovere d human tumour virus, is the causative agent of Kaposi's sarcoma, primary e ffusion lymphoma and some forms of Castleman's disease. KSHV is a rhadinovi rus, and like other rhadinoviruses, it has an extensive e array of regulato ry genes obtained from tire host cell genome. These pirated KSHV proteins i nclude homologues to cellular CD21, three differellt beta -chemokines, IL-6 , BCL-2, several different interferon regulatory factor homologues, Fas-lig and ICE inhibitory protein (FLIP), cyclin D and a G-protein-coupled recepto r, as well as DNA synthetic enzymes including thymidylate synthase, dihydro folate reductase, DNA polymerase, thymidine kinase and ribonucleotide reduc tases. Despite marked differences between KSHV and Epstein-Barr virus, both viruses target man). of the same cellular pathways, but use different stra tegies to achieve the same effects. KSHV proteins have been identified whic h inhibit cell-cycle regulation check-points, apoptosis control mechanisms and the immune response regulatory machinery. Inhibition of these cellular regulatory networks appears to be a defensive means of allowing the virus t o escape fi om innate antiviral immune responses. However, due to the overl apping nature of innate immune and tumour-suppressor pathways, inhibition o f these regulatory networks can lead to unregulated cell proliferation and may contribute to virus-induced tumorigenesis.