Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication

MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR...

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Veröffentlicht in:Journal of virology 2017-05, Vol.91 (10)
Hauptverfasser: Yang, Xi, Li, Hongfeng, Sun, Huahui, Fan, Hongxia, Hu, Yaqi, Liu, Min, Li, Xin, Tang, Hua
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container_issue 10
container_start_page
container_title Journal of virology
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creator Yang, Xi
Li, Hongfeng
Sun, Huahui
Fan, Hongxia
Hu, Yaqi
Liu, Min
Li, Xin
Tang, Hua
description MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection. Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infec
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Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection. Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.</description><identifier>ISSN: 0022-538X</identifier><identifier>EISSN: 1098-5514</identifier><identifier>DOI: 10.1128/JVI.01919-16</identifier><identifier>PMID: 28148795</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>DNA Replication ; DNA, Viral - metabolism ; Gene Expression Regulation, Viral ; Hepadnaviridae ; Hepatitis B - blood ; Hepatitis B - genetics ; Hepatitis B - immunology ; Hepatitis B - virology ; Hepatitis B Core Antigens - analysis ; Hepatitis B e Antigens - metabolism ; Hepatitis B Surface Antigens - metabolism ; Hepatitis B virus ; Hepatitis B virus - genetics ; Hepatitis B virus - immunology ; Hepatitis B virus - physiology ; Hepatitis B, Chronic - blood ; Hepatitis B, Chronic - virology ; Humans ; MicroRNAs - blood ; MicroRNAs - genetics ; MicroRNAs - isolation &amp; purification ; Virus Replication - genetics ; Virus-Cell Interactions</subject><ispartof>Journal of virology, 2017-05, Vol.91 (10)</ispartof><rights>Copyright © 2017 American Society for Microbiology.</rights><rights>Copyright © 2017 American Society for Microbiology. 2017 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-e8269e0091c3250e2621cb818934728f7b811dc6102245ea02d9e285725eea163</citedby><cites>FETCH-LOGICAL-c483t-e8269e0091c3250e2621cb818934728f7b811dc6102245ea02d9e285725eea163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411615/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411615/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28148795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Xi</creatorcontrib><creatorcontrib>Li, Hongfeng</creatorcontrib><creatorcontrib>Sun, Huahui</creatorcontrib><creatorcontrib>Fan, Hongxia</creatorcontrib><creatorcontrib>Hu, Yaqi</creatorcontrib><creatorcontrib>Liu, Min</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Tang, Hua</creatorcontrib><title>Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication</title><title>Journal of virology</title><addtitle>J Virol</addtitle><description>MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection. Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.</description><subject>DNA Replication</subject><subject>DNA, Viral - metabolism</subject><subject>Gene Expression Regulation, Viral</subject><subject>Hepadnaviridae</subject><subject>Hepatitis B - blood</subject><subject>Hepatitis B - genetics</subject><subject>Hepatitis B - immunology</subject><subject>Hepatitis B - virology</subject><subject>Hepatitis B Core Antigens - analysis</subject><subject>Hepatitis B e Antigens - metabolism</subject><subject>Hepatitis B Surface Antigens - metabolism</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B virus - genetics</subject><subject>Hepatitis B virus - immunology</subject><subject>Hepatitis B virus - physiology</subject><subject>Hepatitis B, Chronic - blood</subject><subject>Hepatitis B, Chronic - virology</subject><subject>Humans</subject><subject>MicroRNAs - blood</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - isolation &amp; 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purification</topic><topic>Virus Replication - genetics</topic><topic>Virus-Cell Interactions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Xi</creatorcontrib><creatorcontrib>Li, Hongfeng</creatorcontrib><creatorcontrib>Sun, Huahui</creatorcontrib><creatorcontrib>Fan, Hongxia</creatorcontrib><creatorcontrib>Hu, Yaqi</creatorcontrib><creatorcontrib>Liu, Min</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Tang, Hua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Xi</au><au>Li, Hongfeng</au><au>Sun, Huahui</au><au>Fan, Hongxia</au><au>Hu, Yaqi</au><au>Liu, Min</au><au>Li, Xin</au><au>Tang, Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication</atitle><jtitle>Journal of virology</jtitle><addtitle>J Virol</addtitle><date>2017-05-15</date><risdate>2017</risdate><volume>91</volume><issue>10</issue><issn>0022-538X</issn><eissn>1098-5514</eissn><abstract>MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection. Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>28148795</pmid><doi>10.1128/JVI.01919-16</doi><oa>free_for_read</oa></addata></record>
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subjects DNA Replication
DNA, Viral - metabolism
Gene Expression Regulation, Viral
Hepadnaviridae
Hepatitis B - blood
Hepatitis B - genetics
Hepatitis B - immunology
Hepatitis B - virology
Hepatitis B Core Antigens - analysis
Hepatitis B e Antigens - metabolism
Hepatitis B Surface Antigens - metabolism
Hepatitis B virus
Hepatitis B virus - genetics
Hepatitis B virus - immunology
Hepatitis B virus - physiology
Hepatitis B, Chronic - blood
Hepatitis B, Chronic - virology
Humans
MicroRNAs - blood
MicroRNAs - genetics
MicroRNAs - isolation & purification
Virus Replication - genetics
Virus-Cell Interactions
title Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication
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