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Hepatitis E virus (HEV), a single\u2010stranded RNA virus, is a predominant pathogen of acute hepatitis worldwide. Virus\u2010encoded miRNAs regulate the viral life cycle and escape from the host innate immune system. However, it is rarely known about HEV\u2010encoded miRNA (HEV\u2010miR\u2010A6). In the present study, HEV\u2010miR\u2010A6 was screened by microarray, and further identified in vivo and in vitro. HEV\u2010miR\u2010A6 originated from the methylase (MeT) of HEV open reading frame 1 (ORF1) and was highly conserved in eight HEV genotypes. HEV\u2010miR\u2010A6 expression was growing during HEV replication, and significantly increased in acute hepatitis E patients than convalescence patients. Furthermore, HEV\u2010miR\u2010A6 was specifically detected in liver, spleen, kidney and colon by in situ hybridization. To identify the specificity of HEV\u2010miR\u2010A6, its mutants (HEV\u2010miR\u2010A6M1 and HEV\u2010miR\u2010A6M2) were constructed to change the stem\u2010loop structure. Interestingly, over\u2010expression of HEV\u2010miR\u2010A6 or HEV\u2010miR\u2010A6M1\u00a0significantly facilitated viral replication, while HEV\u2010miR\u2010A6M2, another mutant completely changed the stem\u2010loop structure was invalid. SIRP\u2010\u03b1, a candidate target gene of HEV\u2010miR\u2010A6, was activated when HEV\u2010miR\u2010A6 over\u2010expressed to inhibit the phosphorylation of IRF3, and subsequently suppressed the expression of type I interferon \u03b2 (IFN\u2010\u03b2). The promotion of viral replication by HEV\u2010miR\u2010A6 further identified in vivo. Significant suppression of IFN\u2010\u03b2 production in the serum of HEV\u2010infected mice pre\u2010treated with HEV\u2010miR\u2010A6 was observed. In summary, HEV\u2010miR\u2010A6 activates SIRP\u2010\u03b1 to promote viral replication by inhibition of IFN\u2010\u03b2 expression.<\/jats:p>","DOI":"10.1096\/fj.202101042r","type":"journal-article","created":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T03:43:03Z","timestamp":1639712583000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hepatitis E virus\u2010encoded microRNA promotes viral replication by inhibiting type I interferon"],"prefix":"10.1096","volume":"36","author":[{"given":"Zhongyao","family":"Qian","sequence":"first","affiliation":[{"name":"Medical School Kunming University of Science and Technology  Kunming PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Yang","sequence":"additional","affiliation":[{"name":"Medical School Kunming University of Science and Technology  Kunming PR 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