Autocrine and paracrine promotion of cell survival and virus replication by human herpesvirus 8 chemokines.
Human herpesvirus 8 (HHV-8), which is associated with the endothelial tumor Kaposi's sarcoma, encodes three CC/beta-chemokines. These are expressed early during productive (lytic) infection and are 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 proreplication functions of each chemokine were demonstrated via shRNA-mediated vCCL depletion. The v-chemokines inhibited expression of lytic cycle-induced proapoptotic protein Bim, RNA interference-mediated suppression of which mimicked v-chemokine proreplication 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 prosurvival signaling.
Choi
Young Bong
YB
Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Nicholas
John
J
D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019898:Autocrine Communication / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D054402:Chemokine CCL1 / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D019899:Paracrine Communication / Q000276:immunology*; D010957:Plasmids / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D054401:Receptors, CCR8 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D054402:Chemokine CCL1; D018932:Chemokine CCL2; D008565:Membrane Proteins; D009841:Oligonucleotides; D011518:Proto-Oncogene Proteins; D054401:Receptors, CCR8