Natural defective viruses often play a role in virus infection and replication. Studies of defective viruses could provide insight into virus-related pathogenesis. Defective viruses are often used as tools to define the functions of viral genes. We have identified and characterized a KSHV lytic replication-defective virus (LRDV). This mutant virus, of which more than half of the viral genome have been deleted, is capable of maintaining stable latent viral infection. Cells infected by this virus have higher growth rates, enhanced transformation phenotypes, and reduced apoptosis rates. We have also detected LRDV in a limited numbers of Kaposi's sarcoma tumors, indicating a likely role of LRDV in KSHV-related pathogenesis. We are currently studying the prevalence LRDV in Kaposi's sarcoma tumors and the mechanism of generation of these variants. The isolated LRDV is a very important tool for KSHV virologic studies.