Role of KSHV K1 and RRV R1 in viral pathogenesis

$257,786R01FY2005CANIH

University Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

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Abstract

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) is a multifocal vascular tumor of mixed cellular composition that is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). A new member of the herpesvirus group, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been consistently identified in KS, body cavity-based lymphomas (BCBLs) and some forms of multicentric Castleman's disease (MCD). Analysis of the genomic sequences of rhesus monkey rhadinovirus (RRV) has revealed that RRV is very closely related to Kaposi's sarcoma-associated herpesvirus. RRV naturally infects rhesus macaques and has been shown to induce B-cell hyperplasia in the context of infection with simian immunodeficiency virus (SIV) in macaques. We have studied the transformation properties of the RRV R1 and the KSHV K1 viral oncogenes. We have shown that R1 and K1 are functional homologs capable of inducing transformation, and cellular activation and proliferation events. We propose to dissect the molecular mechanisms by which K1 and R1 cause transformation. These studies involve analyzing the regulation of cellular signal transduction and cellular apoptotic pathways by these viral oncogenes. Detailed functional studies of these proteins will be performed in order to understand the specific role of R1 and K1 in viral replication and oncogenic transformation. We will utilize the RRV genetic system to construct recombinant rhesus rhadinoviruses. We have constructed a recombinant RRVdeltaRl virus for this purpose and will use it to evaluate the relative importance and functional contribution of R1 to viral replicative capacity, tropism, and cellular gene expression. A genetic complementation assay will be performed using the RRVdeltaRI virus and a panel of wild-type and mutant K1 and R1 proteins to map the functional domains of K1 and R1 that are biologically important for viral replication. The proposed study is directed towards understanding the molecular mechanisms of K1 signaling and transformation, and hence the biological role of K1 in KSHV-associated pathogenesis.

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