Antiviral Resistance in Human Cytomegalovirus Due to UL54 Mutations Without UL97 Mutations

Kuenyoul Park1 , Kyu-Hwa Hur2 , Heungsup Sung1 , Sang-Ho Choi3 , Mi-Na Kim1

1Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul
2Department of Laboratory Medicine, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu
3Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Corresponding author : sung@amc.seoul.kr

ABSTRACT

Background: The concurrent detection of human cytomegalovirus (CMV) with UL97 and UL54 mutations is crucial for prescribing adequate antiviral treatment when drug-resistant CMV infection is suspected. We investigated the frequency of resistance-conferring mutations among patients with persistent or recurrent CMV infection and further reviewed the subgroup with UL54 mutations without UL97 mutations.
Methods: Patients with persistent or recurrent CMV infection after 4 weeks of treatment with ganciclovir or foscarnet were consecutively enrolled between November 2012 and May 2019. The direct sequencing of UL97 and UL54 was performed to detect resistance mutations in CMV.
Results: A total of 101 sequencing datasets were obtained from 65 enrolled patients. CMV UL97 and UL54 mutations were detected in 15.4% (10/65) and 9% (6/65) of patients, respectively. The CMV retrieved from two patients (3%) had mutations in both genes. Four patients with CMV UL54 mutations alone had a history of haploidentical peripheral blood stem cell transplantation, and foscarnet was administered for over 4 weeks to these patients; 21.5% of patients had suspected resistant CMV infection with either UL97 or UL54 mutations.
Conclusion: In this study, CMV UL54 mutations but not UL97 mutations were found in patients subjected to prolonged foscarnet administration for CMV disease.

Figures & Tables

 

Table 1. Human cytomegalovirus UL97/UL54 gene mutations observed in this study

Case No.

Year

UL97 mutations (specimen)

UL54 mutations (specimen)

Viral loads

3

2019

A594P (blood)

4.12 log IU/mL

6

2018

F412L (blood)

3.03 log IU/mL

7

2018

L595F (blood)

N408D (blood)

4.40 log copies/mL

11

2017

V715M (blood)

3.34 log copies/mL (blood)

14

2018

L501I (CSF)

4.73 log copies/mL (CSF)

19

2017

L802M (CSF)

5.92 log copies/mL

22

2017

505-506 in frame deletion (anterior chamber fluid)

V787L (blood)

4.72 log copies/mL

29

2017

C603W (blood)

N/A

32

2016

C603W (blood)

N408D/P522S (blood)

3.57 log copies/mL

40

2016

M460V (blood)

5.69 log copies/mL

46

2015

A594V (blood)

4.12 log copies/mL

55

2015

597-600 in frame deletion (blood)

2.42 log copies/mL

60

2014

L595S (blood)

2.42 log copies/mL

65

2013

M460I (blood)

4.59 log copies/mL

40

2019

M460V (blood)

3.99 log IU/mL

46

2015

A594V (blood)

2.42 log copies/mL

55

2014

597-600 in frame deletion (blood)

2.42 log copies/mL

60

2013

L595S (blood)

4.59 log copies/mL

65

2019

M460I (blood)

3.99 log IU/mL

Abbreviations: CSF, cerebrospinal fluid; N/A, not available.