Malignancies in HIV infected individuals are often associated with Kaposi's sarcoma herpesvirus, KSHV (also designated as human herpesvirus-8, HHV-8). Recently a related virus, rhesus rhadinovirus (RRV), has been implicated in lymphoproliferative disease in macaques infected with SW. Although a cell culture system exists for KSHV reactivation, a reliable in vitro system for studying the full viral replication cycle is not available. Accordingly, RRV is a critical complement, because this virus replicates efficiently in rhesus cell cultures and in macaques. The hypothesis for this project is that analysis of key viral transcriptional regulators will define the mechanisms of reactivation of this group of oncogenic herpesviruses. Accordingly, the proposed research is focused on the viral Z gene transcription factor and its mechanistic role in viral reactivation and replication. This project builds on our discovery of the Z transcriptional gene in the KSHV genome. In addition, we recently isolated the cDNA for the Z transcriptional regulatory gene of RRV. With these reagents, we will (1) define the functional domains and the DNA target sequences of these viral regulatory proteins, and (2) examine their roles in reactivation and replication in cell cultures. These virological studies will provide the framework for future investigations using RRV in non-human primates as a model to study viral transcription mechanisms in AIDS associated malignancies.
