P-3:Viral Chemokine signalling in HHV-8 infection

Johns Hopkins University, Baltimore MD

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Abstract

Human herpesvirus-8 (HHV-8, also called KSHV) encodes several proteins that have been implicated in[unreadable] virus-associated pathogenesis. The viral interleukin-6 (vlL-6) and chemokine receptor (vGPCR) have been[unreadable] studied extensively due to their mitogenic and angiogenic properties, their promotion of tumor growth in in[unreadable] vitro and in vivo experimental systems, the proliferative effects of IL-6 signalling on Kaposi's sarcoma (KS),[unreadable] myeloma and primary effusion lymphoma (PEL) cell growth, and the ability of vGPCR to induce KS-like[unreadable] disease in receptor-transduced mice. However, angiogenic activities are also effected by each of the vchemokines[unreadable] (vCCL-1, vCCL-2, vCCL-3), and we have determined that vCCL-1 and vCCL-2 specify antiapoptotic[unreadable] activities, as measured in HHV-8 latently-infected PEL cells challenged with dexamethasone or[unreadable] serum withdrawal. These activities, coupled with the ability of vCCL-2 to regulate the signalling by vGPCR,[unreadable] suggest strongly that the v-chemokines play direct, autocrine roles in lytic replication. We hypothesize that[unreadable] these viral ligands serve to prolong survival of infected cells during lytic replication and to promote[unreadable] intracellular conditions that favor virus production. The anti-apoptotic functions of vCCL-1 and vCCL-2, like[unreadable] similar activities of their cellular counterparts, have not been studied in detail, and the roles of the ligands in[unreadable] virus productive replication have not been investigated. The purpose of this application is to build on our[unreadable] previous work on v-chemokine function and vGPCR signal transduction to investigate the roles of the vCCL-[unreadable] 1 and vCCL-2 in lytic replication and the relevance of vCCL-2:vGPCR interactions to replication efficiency.[unreadable] The specific aims are: (1) to determine the mechanisms of v-chemokine anti-apoptotic signalling, (2) to map[unreadable] the ligand and receptor residues involved in antagonistic vCCL-2:vGPCR interactions, and (3) to determine[unreadable] the roles of the v-chemokines in lytic replication through the generation and utilization in replicationpermissive[unreadable] endothelial cell culture systems of vCCL- and vGPCR-altered HHV-8 recombinant viruses, and[unreadable] by using ribozymes or siRNAs to deplete vCCLs during lytic reactivation in PEL cells. The data from these[unreadable] studies will characterize the roles of the v-chemokines in virus replication and may provide the basis for the[unreadable] development of anti-viral vCCL-2-based vGPCR antagonists.[unreadable]