Autocrine and Paracrine Promotion of Cell Survival and Virus Replication by Human Herpesvirus-8 Chemokines

Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, U.S.A

^* To whom correspondence should be addressed. Email: nichojo{at}jhmi.edu.

	Abstract

Human herpesvirus 8 (HHV-8), associated with the endothelial tumor Kaposi's sarcoma, encodes three CC/-chemokines. These are expressed early during productive (lytic) infection and believed to be involved in immune evasion, in addition to viral pathogenesis via induction of angiogenic cytokines. Here we report that two of the HHV-8 chemokines, CCR8 agonists vCCL-1 and vCCL-2, have direct effects on endothelial survival and virus replication. The v-chemokines stimulated virus replication when added to infected cultures exogenously, and CCR8 knockdown absent v-chemokine supplementation inhibited virus production, indicative of autocrine effects of endogenously-produced vCCLs. This was verified and pro-replication functions of each chemokine demonstrated via shRNA-mediated vCCL depletion. The v-chemokines inhibited expression of lytic cycle-induced pro-apoptotic protein Bim, RNA_i-mediated suppression of which mimicked v-chemokine pro-replication functions. Our data show for the first time that the v-chemokines have direct effects on virus biology, independently of their postulated immune evasion functions, and suggest that in vivo the v-chemokines might play direct roles in Kaposi's sarcomagenesis via paracrine pro-survival signaling.