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De Novo Genotypic Heterogeneity in the UL56 Region in Cytomegalovirus-Infected Tissues: Implications for Primary Letermovir Resistance

Authors
 Horim Jo  ;  Da Eun Kwon  ;  Sang Hoon Han  ;  Seo Yeon Min  ;  Yeon-Mi Hong  ;  Beom Jin Lim  ;  Kyoung Hwa Lee  ;  Jeong-Hyeon Jo 
Citation
 JOURNAL OF INFECTIOUS DISEASES, Vol.221(9) : 1480-1487, 2020-04 
Journal Title
 JOURNAL OF INFECTIOUS DISEASES 
ISSN
 0022-1899 
Issue Date
2020-04
Keywords
cytomegalovirus ; genotype ; letermovir ; resistance ; tissues
Abstract
Background: 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. Methods: 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 552-1330 of the open reading frame of UL56 were amplified with 5 primers and sequenced by a dideoxy fluorescence-based cycle. Results: 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. Conclusions: The treatment difficulties associated with letermovir resistance in a clinical setting need to be verified before its widespread use.
Full Text
https://academic.oup.com/jid/article/221/9/1480/5658434
DOI
10.1093/infdis/jiz642
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Lee, Kyoung Hwa(이경화) ORCID logo https://orcid.org/0000-0003-0033-1398
Lim, Beom Jin(임범진) ORCID logo https://orcid.org/0000-0003-2856-0133
Han, Sang Hoon(한상훈) ORCID logo https://orcid.org/0000-0002-4278-5198
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179158
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