Cidofovir Inhibits Polyomavirus BK Replication in Human Renal Tubular Cells Downstream of Viral Early Gene Expression
The human polyomavirus BK (BKV) causes nephropathy and hemorrhagic cystitis in kidney and bone marrow transplant patients, respectively. The anti‐viral cidofovir (CDV) has been used in small case series but the effects on BKV replication are unclear, since polyomaviruses do not encode viral DNA poly...
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| Veröffentlicht in: | American journal of transplantation 2008-07, Vol.8 (7), p.1413-1422 |
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| creator | Bernhoff, E. Gutteberg, T. J. Sandvik, K. Hirsch, H. H. Rinaldo, C. H. |
| description | The human polyomavirus BK (BKV) causes nephropathy and hemorrhagic cystitis in kidney and bone marrow transplant patients, respectively. The anti‐viral cidofovir (CDV) has been used in small case series but the effects on BKV replication are unclear, since polyomaviruses do not encode viral DNA polymerases. We investigated the effects of CDV on BKV(Dunlop) replication in primary human renal proximal tubule epithelial cells (RPTECs). CDV inhibited the generation of viral progeny in a dose‐dependent manner yielding a 90% reduction at 40 μg/mL. Early steps such as receptor binding and entry seemed unaffected. Initial large T‐antigen transcription and expression were also unaffected, but subsequent intra‐cellular BKV DNA replication was reduced by >90%. Late viral mRNA and corresponding protein levels were also 90% reduced. In uninfected RPTECs, CDV 40 μg/mL reduced cellular DNA replication and metabolic activity by 7% and 11% in BrdU and WST‐1 assays, respectively. BKV infection increased DNA replication to 142% and metabolic activity to 116%, respectively, which were reduced by CDV 40 μg/mL to levels of uninfected untreated RPTECs. Our results show that CDV inhibits BKV DNA replication downstream of large T‐antigen expression and involves significant host cell toxicity. This should be considered in current treatment and drug development.
Cidofovir treatment of BK virus‐infected human renal tubule epithelial cells resulted in inhibition of viral DNA replication and significant host cell toxicity. |
| doi_str_mv | 10.1111/j.1600-6143.2008.02269.x |
| format | Article |
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Cidofovir treatment of BK virus‐infected human renal tubule epithelial cells resulted in inhibition of viral DNA replication and significant host cell toxicity.</description><identifier>ISSN: 1600-6135</identifier><identifier>EISSN: 1600-6143</identifier><identifier>DOI: 10.1111/j.1600-6143.2008.02269.x</identifier><identifier>PMID: 18510636</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Antiviral Agents - pharmacology ; Biological and medical sciences ; BK nephropathy ; BK polyoma virus ; BK virus ; BK Virus - drug effects ; BK virus allograft nephropathy ; BK virus nephritis ; bone marrow transplantation ; Bone marrow, stem cells transplantation. Graft versus host reaction ; Cells, Cultured ; Cidofovir ; Cytosine - analogs & derivatives ; Cytosine - pharmacology ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Viral - drug effects ; Humans ; Infectious diseases ; kidney allograft ; kidney transplantation ; Kidney Tubules, Proximal - cytology ; Kidney Tubules, Proximal - virology ; Medical sciences ; Organophosphonates - pharmacology ; Polyomavirus ; proximal tubule ; real time polymerase chain reaction (PCR) ; real time RT‐PCR ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Surgery of the urinary system ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy ; Viral diseases ; viral infection ; viral load ; viral therapy ; Virus Replication - drug effects</subject><ispartof>American journal of transplantation, 2008-07, Vol.8 (7), p.1413-1422</ispartof><rights>2008 The Authors Journal compilation © 2008 The American Society of Transplantation and the American Society of Transplant Surgeons</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4789-a868afcb15ce01e61192e5391b51b6684b4ab74786bb6b0bf832cbf6acbc7b363</citedby><cites>FETCH-LOGICAL-c4789-a868afcb15ce01e61192e5391b51b6684b4ab74786bb6b0bf832cbf6acbc7b363</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1600-6143.2008.02269.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1600-6143.2008.02269.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20567356$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18510636$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bernhoff, E.</creatorcontrib><creatorcontrib>Gutteberg, T. J.</creatorcontrib><creatorcontrib>Sandvik, K.</creatorcontrib><creatorcontrib>Hirsch, H. H.</creatorcontrib><creatorcontrib>Rinaldo, C. H.</creatorcontrib><title>Cidofovir Inhibits Polyomavirus BK Replication in Human Renal Tubular Cells Downstream of Viral Early Gene Expression</title><title>American journal of transplantation</title><addtitle>Am J Transplant</addtitle><description>The human polyomavirus BK (BKV) causes nephropathy and hemorrhagic cystitis in kidney and bone marrow transplant patients, respectively. The anti‐viral cidofovir (CDV) has been used in small case series but the effects on BKV replication are unclear, since polyomaviruses do not encode viral DNA polymerases. We investigated the effects of CDV on BKV(Dunlop) replication in primary human renal proximal tubule epithelial cells (RPTECs). CDV inhibited the generation of viral progeny in a dose‐dependent manner yielding a 90% reduction at 40 μg/mL. Early steps such as receptor binding and entry seemed unaffected. Initial large T‐antigen transcription and expression were also unaffected, but subsequent intra‐cellular BKV DNA replication was reduced by >90%. Late viral mRNA and corresponding protein levels were also 90% reduced. In uninfected RPTECs, CDV 40 μg/mL reduced cellular DNA replication and metabolic activity by 7% and 11% in BrdU and WST‐1 assays, respectively. BKV infection increased DNA replication to 142% and metabolic activity to 116%, respectively, which were reduced by CDV 40 μg/mL to levels of uninfected untreated RPTECs. Our results show that CDV inhibits BKV DNA replication downstream of large T‐antigen expression and involves significant host cell toxicity. This should be considered in current treatment and drug development.
Cidofovir treatment of BK virus‐infected human renal tubule epithelial cells resulted in inhibition of viral DNA replication and significant host cell toxicity.</description><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>BK nephropathy</subject><subject>BK polyoma virus</subject><subject>BK virus</subject><subject>BK Virus - drug effects</subject><subject>BK virus allograft nephropathy</subject><subject>BK virus nephritis</subject><subject>bone marrow transplantation</subject><subject>Bone marrow, stem cells transplantation. Graft versus host reaction</subject><subject>Cells, Cultured</subject><subject>Cidofovir</subject><subject>Cytosine - analogs & derivatives</subject><subject>Cytosine - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Gene Expression Regulation, Viral - drug effects</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>kidney allograft</subject><subject>kidney transplantation</subject><subject>Kidney Tubules, Proximal - cytology</subject><subject>Kidney Tubules, Proximal - virology</subject><subject>Medical sciences</subject><subject>Organophosphonates - pharmacology</subject><subject>Polyomavirus</subject><subject>proximal tubule</subject><subject>real time polymerase chain reaction (PCR)</subject><subject>real time RT‐PCR</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>Surgery of the urinary system</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><subject>Viral diseases</subject><subject>viral infection</subject><subject>viral load</subject><subject>viral therapy</subject><subject>Virus Replication - drug effects</subject><issn>1600-6135</issn><issn>1600-6143</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkMFOGzEQQK2qVaHQX6h8aW9Z7HXW6z30ACElQCQQCr1aY-NVHXntYGeb5O_rJVG4di4zGr8Zjx5CmJKC5rhYFpQTMuJ0zIqSEFGQsuRNsf2ATo8PH481q07Ql5SWhNC6FOVndEJFRQln_BT1E_sS2vDXRnzr_1hl1wk_BrcLHeRen_DVPX4yK2c1rG3w2Ho86zvwuenB4UWvegcRT4xzCV-HjU_raKDDocW_bczEFKLb4RvjDZ5uV9GklNeco08tuGS-HvIZev41XUxmo_nDze3kcj7S41o0IxBcQKsVrbQh1HBKm9JUrKGqoopzMVZjUHVGuVJcEdUKVmrVctBK14pxdoZ-7PeuYnjtTVrLziadbwVvQp8kbeqGi7rOoNiDOoaUomnlKtoO4k5SIgflcikHm3IwKwfl8k253ObRb4c_etWZl_fBg-MMfD8AkDS4NoLXNh25klS8ZtXA_dxzG-vM7r8PkJd3i6Fi_wDOqZ2o</recordid><startdate>200807</startdate><enddate>200807</enddate><creator>Bernhoff, E.</creator><creator>Gutteberg, T. J.</creator><creator>Sandvik, K.</creator><creator>Hirsch, H. H.</creator><creator>Rinaldo, C. H.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>200807</creationdate><title>Cidofovir Inhibits Polyomavirus BK Replication in Human Renal Tubular Cells Downstream of Viral Early Gene Expression</title><author>Bernhoff, E. ; Gutteberg, T. J. ; Sandvik, K. ; Hirsch, H. H. ; Rinaldo, C. H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4789-a868afcb15ce01e61192e5391b51b6684b4ab74786bb6b0bf832cbf6acbc7b363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>BK nephropathy</topic><topic>BK polyoma virus</topic><topic>BK virus</topic><topic>BK Virus - drug effects</topic><topic>BK virus allograft nephropathy</topic><topic>BK virus nephritis</topic><topic>bone marrow transplantation</topic><topic>Bone marrow, stem cells transplantation. Graft versus host reaction</topic><topic>Cells, Cultured</topic><topic>Cidofovir</topic><topic>Cytosine - analogs & derivatives</topic><topic>Cytosine - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Gene Expression Regulation, Viral - drug effects</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>kidney allograft</topic><topic>kidney transplantation</topic><topic>Kidney Tubules, Proximal - cytology</topic><topic>Kidney Tubules, Proximal - virology</topic><topic>Medical sciences</topic><topic>Organophosphonates - pharmacology</topic><topic>Polyomavirus</topic><topic>proximal tubule</topic><topic>real time polymerase chain reaction (PCR)</topic><topic>real time RT‐PCR</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>Surgery of the urinary system</topic><topic>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</topic><topic>Viral diseases</topic><topic>viral infection</topic><topic>viral load</topic><topic>viral therapy</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bernhoff, E.</creatorcontrib><creatorcontrib>Gutteberg, T. J.</creatorcontrib><creatorcontrib>Sandvik, K.</creatorcontrib><creatorcontrib>Hirsch, H. H.</creatorcontrib><creatorcontrib>Rinaldo, C. 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H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cidofovir Inhibits Polyomavirus BK Replication in Human Renal Tubular Cells Downstream of Viral Early Gene Expression</atitle><jtitle>American journal of transplantation</jtitle><addtitle>Am J Transplant</addtitle><date>2008-07</date><risdate>2008</risdate><volume>8</volume><issue>7</issue><spage>1413</spage><epage>1422</epage><pages>1413-1422</pages><issn>1600-6135</issn><eissn>1600-6143</eissn><abstract>The human polyomavirus BK (BKV) causes nephropathy and hemorrhagic cystitis in kidney and bone marrow transplant patients, respectively. The anti‐viral cidofovir (CDV) has been used in small case series but the effects on BKV replication are unclear, since polyomaviruses do not encode viral DNA polymerases. We investigated the effects of CDV on BKV(Dunlop) replication in primary human renal proximal tubule epithelial cells (RPTECs). CDV inhibited the generation of viral progeny in a dose‐dependent manner yielding a 90% reduction at 40 μg/mL. Early steps such as receptor binding and entry seemed unaffected. Initial large T‐antigen transcription and expression were also unaffected, but subsequent intra‐cellular BKV DNA replication was reduced by >90%. Late viral mRNA and corresponding protein levels were also 90% reduced. In uninfected RPTECs, CDV 40 μg/mL reduced cellular DNA replication and metabolic activity by 7% and 11% in BrdU and WST‐1 assays, respectively. BKV infection increased DNA replication to 142% and metabolic activity to 116%, respectively, which were reduced by CDV 40 μg/mL to levels of uninfected untreated RPTECs. Our results show that CDV inhibits BKV DNA replication downstream of large T‐antigen expression and involves significant host cell toxicity. This should be considered in current treatment and drug development.
Cidofovir treatment of BK virus‐infected human renal tubule epithelial cells resulted in inhibition of viral DNA replication and significant host cell toxicity.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>18510636</pmid><doi>10.1111/j.1600-6143.2008.02269.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Antiviral Agents - pharmacology Biological and medical sciences BK nephropathy BK polyoma virus BK virus BK Virus - drug effects BK virus allograft nephropathy BK virus nephritis bone marrow transplantation Bone marrow, stem cells transplantation. Graft versus host reaction Cells, Cultured Cidofovir Cytosine - analogs & derivatives Cytosine - pharmacology Dose-Response Relationship, Drug Gene Expression Regulation, Viral - drug effects Humans Infectious diseases kidney allograft kidney transplantation Kidney Tubules, Proximal - cytology Kidney Tubules, Proximal - virology Medical sciences Organophosphonates - pharmacology Polyomavirus proximal tubule real time polymerase chain reaction (PCR) real time RT‐PCR Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Surgery of the urinary system Transfusions. Complications. Transfusion reactions. Cell and gene therapy Viral diseases viral infection viral load viral therapy Virus Replication - drug effects |
| title | Cidofovir Inhibits Polyomavirus BK Replication in Human Renal Tubular Cells Downstream of Viral Early Gene Expression |
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