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Experimental and clinical evidence suggests that vIL-6 is important for the onset and\/or progression of HHV-8-associated endothelial-cell and B-cell pathologies, including AIDS-associated Kaposi\u2019s sarcoma and multicentric Castleman\u2019s disease. The protein is unusual in its poor secretion from cells and its intracellular activity; it interacts, directly or indirectly, with a number of proteins beyond the IL-6 signal transducer, gp130, and can mediate activities through these interactions in the endoplasmic reticulum. Here, we report the characterization with respect to protein interactions and signal-transducing activity of a panel of vIL-6 variants and utilization of HHV-8 mutant viruses expressing selected variants in phenotypic analyses. Our findings establish the importance of vIL-6 in HHV-8 productive replication and the contributions of individual vIL-6-protein interactions to HHV-8 lytic biology. This work furthers understanding of the biological significance of vIL-6 and its unique intracellular interactions.<\/jats:p>","DOI":"10.1128\/jvi.00909-20","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T13:01:11Z","timestamp":1594904471000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication"],"prefix":"10.1128","volume":"94","author":[{"given":"Qian","family":"Li","sequence":"first","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiwang","family":"Xiang","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center at 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