{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T12:47:14Z","timestamp":1759063634571,"version":"3.37.3"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Basic Science Research Program"},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009950","name":"Ministry of Education","doi-asserted-by":"publisher","award":["NRF-2017R1D1A1B03032844"],"award-info":[{"award-number":["NRF-2017R1D1A1B03032844"]}],"id":[{"id":"10.13039\/100009950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Letermovir, an inhibitor of unique long (UL)56-encoded cytomegalovirus (CMV)-terminase, shows prophylactic effects with low-grade adverse events in hematopoietic stem cell transplant recipients. Despite few case reports on acquired letermovir resistance, the frequency of de novo amino acid (A.A.) changes encoded by UL56 in CMV-infected tissues is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed CMV UL56 sequences between the conserved region IV and variable region I in 175 formalin-fixed, paraffin-embedded tissues obtained from 147 patients showing positive CMV immunochemical staining between November 2012 and October 2016. Nucleotides 552\u20131330 of the open reading frame of UL56 were amplified with 5 primers and sequenced by a dideoxy fluorescence-based cycle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six (3.4%) tissues from 4 (2.7%) patients harbored A.A. substitutions. There were no known potent resistant mutations. However, we found C325Y in 2 tissues from 1 patient, along with other mutations. Four novel A.A. changes, which have not been observed in previous in vitro experiments, were identified (T244I, S301T, G312V, and M434I). Most (9 of 11, 81.8%) of the A.A. changes occurred between the codons 301 and 325 present between the conserved regions V and VI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The treatment difficulties associated with letermovir resistance in a clinical setting need to be verified before its widespread use.<\/jats:p><\/jats:sec>","DOI":"10.1093\/infdis\/jiz642","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T12:09:20Z","timestamp":1575461360000},"page":"1480-1487","source":"Crossref","is-referenced-by-count":11,"title":["De Novo Genotypic Heterogeneity in the UL56 Region in Cytomegalovirus-Infected Tissues: Implications for Primary Letermovir Resistance"],"prefix":"10.1093","volume":"221","author":[{"given":"Horim","family":"Jo","sequence":"first","affiliation":[{"name":"Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da Eun","family":"Kwon","sequence":"first","affiliation":[{"name":"Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5961-6526","authenticated-orcid":false,"given":"Sang Hoon","family":"Han","sequence":"first","affiliation":[{"name":"Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seo Yeon","family":"Min","sequence":"first","affiliation":[{"name":"Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeon-Mi","family":"Hong","sequence":"first","affiliation":[{"name":"Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beom Jin","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoung Hwa","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong-Hyeon","family":"Jo","sequence":"first","affiliation":[{"name":"Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,12,5]]},"reference":[{"key":"2020040710053406500_CIT0001","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/path.4437","article-title":"The pathogenesis of human cytomegalovirus","volume":"235","author":"Griffiths","year":"2015","journal-title":"J Pathol"},{"key":"2020040710053406500_CIT0002","doi-asserted-by":"crossref","first-page":"e13512","DOI":"10.1111\/ctr.13512","article-title":"Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice","volume":"33","author":"Razonable","year":"2019","journal-title":"Clin Transplant"},{"key":"2020040710053406500_CIT0003","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1182\/blood-2015-11-679639","article-title":"Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis","volume":"127","author":"Teira","year":"2016","journal-title":"Blood"},{"key":"2020040710053406500_CIT0004","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1111\/ajt.15371","article-title":"Improving our mechanistic understanding of the indirect effects of CMV infection in transplant recipients","volume":"19","author":"L\u2019Huillier","year":"2019","journal-title":"Am J Transplant"},{"key":"2020040710053406500_CIT0005","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1016\/S1473-3099(19)30107-0","article-title":"Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7","volume":"19","author":"Ljungman","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"2020040710053406500_CIT0006","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1056\/NEJMoa1706640","article-title":"Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation","volume":"377","author":"Marty","year":"2017","journal-title":"N Engl J Med"},{"key":"2020040710053406500_CIT0007","doi-asserted-by":"crossref","DOI":"10.1093\/cid\/ciz490","article-title":"A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation","author":"Ljungman","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2020040710053406500_CIT0008","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1056\/NEJMoa1309533","article-title":"Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation","volume":"370","author":"Chemaly","year":"2014","journal-title":"N Engl J Med"},{"key":"2020040710053406500_CIT0009","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.2147\/IDR.S180908","article-title":"Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review","volume":"12","author":"El Helou","year":"2019","journal-title":"Infect Drug Resist"},{"key":"2020040710053406500_CIT0010","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000002785","article-title":"Letermovir as salvage therapy for CMV infection in transplant recipients","author":"Phoompoung","year":"2019","journal-title":"Transplantation"},{"key":"2020040710053406500_CIT0011","article-title":"Use","volume":"63:e02337\u201318","author":"Turner","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2020040710053406500_CIT0012","doi-asserted-by":"crossref","first-page":"3060","DOI":"10.1111\/ajt.15135","article-title":"Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection","volume":"18","author":"Cherrier","year":"2018","journal-title":"Am J Transplant"},{"key":"2020040710053406500_CIT0013","article-title":"Caution is required before recommending wide use of letermovir as salvage therapy for cytomegalovirus diseases","volume":"63:e00178\u201319","author":"Frange","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2020040710053406500_CIT0014","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/infdis\/jiv352","article-title":"Characterization of cytomegalovirus breakthrough events in a phase 2 prophylaxis trial of letermovir (AIC246, MK 8228)","volume":"213","author":"Lischka","year":"2016","journal-title":"J Infect Dis"},{"key":"2020040710053406500_CIT0015","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1186\/s12879-019-4016-1","article-title":"Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient","volume":"19","author":"Jung","year":"2019","journal-title":"BMC Infect Dis"},{"key":"2020040710053406500_CIT0016","doi-asserted-by":"crossref","first-page":"104549","DOI":"10.1016\/j.antiviral.2019.104549","article-title":"In-depth genomic analyses identified novel letermovir resistance-associated substitutions in the cytomegalovirus UL56 and UL89 gene products","volume":"169","author":"Komatsu","year":"2019","journal-title":"Antiviral Res"},{"key":"2020040710053406500_CIT0017","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1128\/AAC.01794-13","article-title":"Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure","volume":"58","author":"Goldner","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2020040710053406500_CIT0018","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/femsre\/fuy004","article-title":"The human cytomegalovirus terminase complex as an antiviral target: a close-up view","volume":"42","author":"Ligat","year":"2018","journal-title":"FEMS Microbiol Rev"},{"key":"2020040710053406500_CIT0019","doi-asserted-by":"crossref","first-page":"e2019001","DOI":"10.4084\/mjhid.2019.001","article-title":"In vivo emergence of UL56 C325Y cytomegalovirus resistance to letermovir in a patient with acute myeloid leukemia after hematopoietic cell transplantation","volume":"11","author":"Frietsch","year":"2019","journal-title":"Mediterr J Hematol Infect Dis"},{"key":"2020040710053406500_CIT0020","article-title":"Cytomegalovirus","volume":"4:1\u201326","author":"Dioverti","year":"2016","journal-title":"Microbiol Spectr"},{"key":"2020040710053406500_CIT0021","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1093\/cid\/cit096","article-title":"Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard is predictive of CMV disease resolution in transplant recipients","volume":"56","author":"Razonable","year":"2013","journal-title":"Clin Infect Dis"},{"key":"2020040710053406500_CIT0022","doi-asserted-by":"crossref","first-page":"4362","DOI":"10.1128\/JCM.39.12.4362-4369.2001","article-title":"Quantification of human cytomegalovirus DNA in bone marrow transplant recipients by real-time PCR","volume":"39","author":"Griscelli","year":"2001","journal-title":"J Clin Microbiol"},{"key":"2020040710053406500_CIT0023","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/ajh.2830460213","article-title":"Systematic use of automated fluorescence-based sequence analysis of amplified genomic DNA for rapid detection of point mutations","volume":"46","author":"Tamary","year":"1994","journal-title":"Am J Hematol"},{"key":"2020040710053406500_CIT0024","doi-asserted-by":"crossref","first-page":"58","DOI":"10.2144\/000112499","article-title":"Improved DNA sequencing quality and efficiency using an optimized fast cycle sequencing protocol","volume":"43","author":"Platt","year":"2007","journal-title":"Biotechniques"},{"key":"2020040710053406500_CIT0025","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1101\/gr.070227.107","article-title":"Quality scores and SNP detection in sequencing-by-synthesis systems","volume":"18","author":"Brockman","year":"2008","journal-title":"Genome Res"},{"key":"2020040710053406500_CIT0026","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/978-1-61779-461-2_19","article-title":"Capillary electrophoresis of Big-Dye terminator sequencing reactions for human mtDNA Control Region haplotyping in the identification of human remains","volume":"830","author":"Montesino","year":"2012","journal-title":"Methods Mol Biol"},{"key":"2020040710053406500_CIT0027","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1373\/clinchem.2014.223040","article-title":"Sequence artifacts in DNA from formalin-fixed tissues: causes and strategies for minimization","volume":"61","author":"Do","year":"2015","journal-title":"Clin Chem"},{"key":"2020040710053406500_CIT0028","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.antiviral.2019.01.011","article-title":"Clinical development of letermovir and maribavir: overview of human cytomegalovirus drug resistance","volume":"163","author":"Piret","year":"2019","journal-title":"Antiviral Res"},{"key":"2020040710053406500_CIT0029","doi-asserted-by":"crossref","first-page":"6588","DOI":"10.1128\/AAC.01623-15","article-title":"Rapid in vitro evolution of human cytomegalovirus UL56 mutations that confer letermovir resistance","volume":"59","author":"Chou","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2020040710053406500_CIT0030","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.antiviral.2017.10.019","article-title":"A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance","volume":"148","author":"Chou","year":"2017","journal-title":"Antiviral Res"},{"key":"2020040710053406500_CIT0031","article-title":"New locus of drug resistance in the human cytomegalovirus UL56 gene revealed by in vitro exposure to letermovir and ganciclovir","volume":"62:e00922\u201318","author":"Chou","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2020040710053406500_CIT0032","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.antiviral.2015.01.006","article-title":"Phenotypic characterization of two naturally occurring human cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir","volume":"116","author":"Goldner","year":"2015","journal-title":"Antiviral Res"},{"key":"2020040710053406500_CIT0033","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.antiviral.2016.06.008","article-title":"Impact of glycoprotein B genotype and naturally occurring ORF UL56 polymorphisms upon susceptibility of clinical human cytomegalovirus isolates to letermovir","volume":"132","author":"Lischka","year":"2016","journal-title":"Antiviral Res"},{"key":"2020040710053406500_CIT0034","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1177\/135965350801300504","article-title":"Putative functional domains of human cytomegalovirus pUL56 involved in dimerization and benzimidazole D-ribonucleoside activity","volume":"13","author":"Champier","year":"2008","journal-title":"Antivir Ther"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiz642\/31579188\/jiz642.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/221\/9\/1480\/33020235\/jiz642.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/221\/9\/1480\/33020235\/jiz642.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T17:19:04Z","timestamp":1665163144000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/221\/9\/1480\/5658434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,5]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,12,5]]},"published-print":{"date-parts":[[2020,4,7]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiz642","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"type":"print","value":"0022-1899"},{"type":"electronic","value":"1537-6613"}],"subject":[],"published-other":{"date-parts":[[2020,5,1]]},"published":{"date-parts":[[2019,12,5]]}}}