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. Author manuscript; available in PMC: 2026 Aug 18.
Published in final edited form as: Antiviral Res. 2025 Dec 31;246:106340. doi: 10.1016/j.antiviral.2025.106340

A new locus of foscarnet resistance in the cytomegalovirus UL54 DNA polymerase gene among uncharacterized mutations in recent clinical trials

Sunwen Chou a,b, Alexis Minyard a, Justin Watanabe a
PMCID: PMC13478573  NIHMSID: NIHMS2202637  PMID: 41482062

Abstract

In two recent Phase 3 clinical trials of maribavir that also involved existing standard therapies, many uncharacterized cytomegalovirus UL54 DNA polymerase genetic variants were encountered. Six UL54 mutations were selected for phenotyping, based on proximity to published resistance loci and quality of sequencing information. UL54 amino acid substitutions E949K and E949Q conferred foscarnet resistance with slightly decreased ganciclovir and cidofovir susceptibility, representing a novel palm domain resistance locus. UL54 N498S and P598S mutants had slight decreases in ganciclovir and cidofovir susceptibility, with N498S also having a slightly decreased foscarnet susceptibility. No drug resistance was attributed to A786V and A928V. Retesting published phenotypes for UL54 mutants D515E, D542E, A543V and A928T revealed some discordant findings, including ganciclovir resistance for D542E and A543V, and no drug resistance for D515E and A928T. These genotype-phenotype correlations add to the evidence base for clinical diagnostic testing of cytomegalovirus drug resistance.

1. Introduction

As a principal target of antiviral therapy for human cytomegalovirus (CMV), the viral UL54 DNA polymerase has been a sustained focus of attention. After extensive phenotyping of UL54 gene mutations encountered in vitro and in clinical trials, a detailed map has been developed of mutations that confer resistance to one or more of the licensed antivirals targeting this gene product (ganciclovir, valganciclovir, foscarnet and cidofovir). This information is referenced in clinical guidelines (Kotton et al., 2025) and available online (Tilloy et al., 2024) as the basis for diagnosing drug resistance in treated patients.

Despite the volume of published information, many uncharacterized UL54 sequence variants continue to be encountered in large scale clinical trials. In the two recent Phase 3 clinical trials of maribavir that also involved traditional therapies, 243 unknown UL54 variants were listed, including 49 detected after exposure to study drug (Chou et al., 2024; Chou et al., 2025). Although the phenotyping of specific CMV mutations has benefited from many technical advances, it remains impractical to phenotype such large numbers of variants. Additionally, previous experience has shown that irreproducible sequencing artifacts are frequently reported from clinical trials that could result in unproductive work (Chou et al., 2014; Chou et al., 2022; Douglas et al., 2020). Prioritization of mutations for phenotyping is necessary. The aim of new phenotyping work is to add to the database of proven resistance mutations to improve the accuracy of CMV genotypic resistance testing.

Published genotype-phenotype correlations benefit from ongoing quality control initiatives. Phenotypic assays used to read out resistance levels for specific mutations vary widely in calibration to known controls, replicates of testing and statistical confidence. In cases where inconsistent phenotypes have been published for the same or similarly located mutations, additional independent testing is warranted. A secondary aim of this study is to provide such information on selected UL54 variants.

2. Methods

2.1. Selection of mutations for phenotyping

As with previous clinical trials (Chou et al., 2014), mutations from the Phase 3 maribavir trials were prioritized for phenotyping based on proximity to known resistance mutations, location in conserved functional and structural domains and post-treatment change from a baseline sequence. Given the many sequence artifacts noted in previous clinical trials (Chou et al., 2014; Chou et al., 2022; Douglas et al., 2020), lower priority was assigned to mutations appearing as partial sequence populations in low copy number specimens, and where the available sequence chromatograms had low quality scores.

Published mutations were selected for additional phenotyping where mutations at the same or nearby codons in UL54 functional or structural domains are reported to have divergent phenotypes.

2.2. Construction of recombinant viral clones

UL54 mutations were introduced into a baseline bacterial artificial chromosome (BAC) clone BD1, derived from laboratory strain AD169 and incorporating a secreted alkaline phosphatase (SEAP) reporter gene, as previously described (Chou, 2017). This involved a bacterial host (SW105) modified for conditional induction of recombinogenic genes (exo, bet, gam). A kanamycin resistance cassette flanked by Frt motifs and subsequently removed by Flp recombinase was used to facilitate cloning.

2.3. Phenotyping of mutant recombinant viral clones

ARPEp cells (ARPE-19 transduced to express the platelet-derived growth factor alpha receptor) were used for phenotypic assays. Following published methods (Chou and Watanabe, 2024), mutant BAC clones were transfected into ARPEp cells to reconstitute live virus stock, the entire UL54 coding sequence of which was checked for presence of the intended mutation and absence of extraneous changes. Calibrated low-multiplicity inocula (MOI ~0.01) of cell-free virus stock were used to inoculate rows of 24-well plates of confluent ARPEp cells and incubated under drug concentrations ranging from 0 to approximately 4 times the 50% effective concentration (EC50). Culture supernatants were collected for assay of SEAP activity at 1 day (from the no-drug well before onset of viral replication) to calibrate the viral inoculum and at 6 to 7 days to assay for viral growth with and without drug. The baseline wild type strain and a mutant known to be resistant to ganciclovir, cidofovir and foscarnet (UL54 D981del2 = in-frame deletion of codons 981–982) (Chou et al., 2024) were included in every assay setup as controls. The EC50 value was calculated as the drug concentration required to reduce SEAP activity by 50% from the well with no drug. A minimum of 7 replicates of testing over 4 separate setup dates for each of the drugs cidofovir, ganciclovir and foscarnet were specified to allow for variation in cell culture conditions. EC50 values were tabulated as mean and standard deviation values, and significant differences from those of the matching wild type control in the same assay setup were determined using the Student t-test (2-tailed, unequal variance). An EC50 increase of ≥2-fold over that of wild type baseline was used to define drug resistance. Comparative growth curves of mutant viruses were determined as previously described (Chou, 2017), by measuring the supernatant SEAP activity at day 1 (reflecting the actual MOI) and each of days 4 to 8.

3. Results

3.1. Mutations selected for phenotyping

From the lists of sequence variants in published supplementary tables from two Phase 3 maribavir clinical trials (Chou et al., 2024; Chou et al., 2025), six uncharacterized UL54 amino acid substitutions were selected for phenotyping, located in the exonuclease (N498S), amino-terminal (P598S), finger (A786V) and palm (A928V, E949K/Q) domains of the DNA polymerase gene (Kotton et al., 2025) and are in proximity of mutations previously reported to confer resistance. Among UL54 amino acid substitutions with a published phenotype, and unrelated to the maribavir trials, four were selected for re-testing because of inconclusive or borderline phenotypes (D515E), exonuclease domain substitutions without the usual finding of ganciclovir-cidofovir cross-resistance (D542E, A543V), or a phenotype discordant with another mutation at the same codon (A928T).

3.2. Drug susceptibility phenotypes of selected variants

Each of the tested mutations was readily transferred to new BAC clones and transfected into ARPEp cells to yield infectious CMV stock with the intended UL54 DNA polymerase gene sequence as verified by Sanger sequencing. After many replicates of susceptibility testing on 6 to 14 (median 7) separate setup dates per mutant using the established SEAP-reporter yield reduction assay, EC50 values for cidofovir, foscarnet and ganciclovir were determined as shown in Table 1. The resistant control strain (D981del2) again showed the expected triple drug resistance in every assay setup. Among the 6 newly phenotyped mutations from the maribavir clinical trials, E949K and E949Q were notable for conferring foscarnet resistance. The 5.8-fold increased foscarnet EC50 for E949K is relatively high compared with the 3-fold increase observed for the control D981del2 mutant and other foscarnet resistance mutations commonly detected in clinical samples (Chou, 2017; Komatsu et al., 2014; Tilloy et al., 2024). The E949K/Q mutants also showed slight but statistically significant elevations of EC50s for cidofovir and ganciclovir that are below the 2-fold cutoff typically used to define drug resistance (Tilloy et al., 2024). These slight EC50 elevations (less than 2-fold) for cidofovir and ganciclovir were also observed for the tested mutants N498S and P598S, with N498S additionally showing the same for foscarnet. Sequence variants A786V and A928V showed no indication of any EC50 shift from baseline.

Table 1.

Genotypes and phenotypes of UL54 recombinant viruses

Strain1 Genotype2 Cidofovir EC50, μM Ganciclovir EC50, μM Foscarnet EC50, μM
Mean SD N Ratio3 Mean SD N Ratio3 Mean SD N Ratio3
Control strains
 4198 WT 0.37 0.07 67 1.38 0.23 30 40 7 42
 4376 D981del2 1.18 0.23 61 3.2 10.3 2.1 36 7.5 120 25 43 3.0
New recombinants (N=10)
 4558 N498S 0.71 0.15 14 1.8 2.43 0.64 14 1.7 69 7 15 1.7
 4609 D515E 0.41 0.11 12 1.1 1.29 0.17 12 1.0 34 6 17 0.9
 4610 D542E 4.61 0.84 20 13 4.53 0.64 16 3.5 22 5 16 0.5
 4629 A543V 1.19 0.32 25 3.2 2.88 0.63 25 2.1 28 4 16 0.7
 4559 P598S 0.68 0.11 16 1.7 2.56 0.54 14 1.9 29 4 13 0.7
 4561 A786V 0.43 0.04 12 1.0 1.35 0.27 14 1.0 46 8 11 1.1
 4576 A928T 0.35 0.07 14 1.0 1.28 0.30 12 0.9 35 6 12 0.9
 4562 A928V 0.41 0.07 12 1.0 1.40 0.27 12 1.0 45 7 11 1.1
 4589 E949K 0.59 0.11 12 1.6 2.52 0.36 13 1.7 234 39 16 5.8
 4563 E949Q 0.64 0.16 16 1.7 2.04 0.30 14 1.4 145 19 14 3.7
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1

Serial number of recombinant CMV strain

2

UL54 amino acid substitution shown. WT = wild type.

D981del2 = in frame deletion of codons 981–982

SD = Standard deviation of the EC50 values; N = Number of replicate assays

3

Ratio = EC50 of mutant virus/EC50 of wild type control.

(based on the WT control assays matched to each mutant strain)

Bold indicates EC50 ≥2x WT control, used as cutoff to define drug resistance

All EC50 ratios ≥1.4 or ≤0.7 denote a significant EC50 shift from WT

(p<1 × 10−4, Student t test, 2-tailed unequal variances)

Newly assayed phenotypes for known mutations revealed some discordance with published data. D515E conferred no EC50 shifts, in contrast to the reported low-grade ganciclovir resistance (Fischer et al., 2015). D542E and A543V both conferred cidofovir and low-grade ganciclovir resistance (EC50s elevated from WT, p<4×10−12 for each mutant and drug), in contrast to their published lack of ganciclovir resistance (James et al., 2013; Santos Bravo et al., 2022). We could not confirm any of the triple-drug resistance attributed to A928T (Santos Bravo et al., 2022).

3.3. Comparative growth phenotypes

At first transfection and during susceptibility assays, there was appreciable growth attenuation noted for the D542E mutant as published (James et al., 2013), and for E949K. Comparative growth curves (Figure 1) confirmed that the D542E and E949K mutants were significantly growth-attenuated as compared with the wild type control and other mutants such as A543V, E949Q, and the resistant control mutant D981del2.

Figure 1. Comparative growth curves of recombinant viruses.

Figure 1

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Cell -free virus stocks of strains with the indicated UL54 amino acid substitutions were inoculated at equivalent multiplicity of infection of 0.01 as judged by supernatant SEAP activity at 1 day. Culture supernatants were collected daily for SEAP assay on days 4 to 8 as a measure of viral growth. Results are plotted as the mean and standard deviation of 4 simultaneous replicates.

4. Discussion

Even with a highly populated CMV UL54 DNA polymerase drug resistance mutation map, large scale clinical trials occasionally reveal new resistance loci such as the E949K/Q reported here (Chou et al., 2024; Chou et al., 2025). The mutations selected for phenotyping were observed at baseline with prior exposure to standard antiviral therapy, except for E949K that was observed as emergent after foscarnet rescue.

E949K/Q are located near the amino acid substitution E951D that was selected in vitro to confer foscarnet resistance and borderline ganciclovir susceptibility (Chou, 2017). Another nearby substitution E946L was also selected in vitro to confer foscarnet resistance (Gilbert et al., 2011), but resistance mutations in this vicinity have not been reported in clinical sequences. Structure modeling tools such as AlphaFold 3 (Abramson et al., 2024) map E949K/Q to the palm domain of the polymerase (Figure 2), in spatial proximity to other known resistance mutations such as V715M and G841A (Chou et al., 2007; Topalis et al., 2016). The higher foscarnet EC50 of E949K correlates with significant growth attenuation, but E949Q appears to be less resistant and less growth-attenuated. Growth-impaired mutants such as E949K and D542E may be less likely to be selected if other mutations confer similar levels of resistance at lower fitness cost, and less likely to persist if the selecting drug is withdrawn.

Figure 2. CMV DNA polymerase structure model.

Figure 2

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Cartoon representation of the model predicted by AlphaFold 3 (Abramson et al., 2024) from the UL54 and UL44 amino acid sequences and visualized in UCSF ChimeraX (Pettersen et al., 2021). Recognized structure domains are labeled and colored, and individual residues where mutations confer drug resistance are marked in contrasting colors.

N498S is near mutation N495K (Figure 2) phenotyped as foscarnet-resistant (Chou, 2017; Ducancelle et al., 2006) and mutations P497S and K500N phenotyped as low-grade resistant to ganciclovir and cidofovir (Chou et al., 2022; Gilbert et al., 2011). The observed subtle EC50 shifts are consistent with an amino acid substitution at the periphery of an exonuclease domain (Figure 2). The mutation P598S maps to an amino-terminal domain near mutations C590F (Chou et al., 2024) and F595I (Gilbert et al., 2011) that confer foscarnet resistance, and H600L that reportedly confers triple-drug resistance (Park et al., 2022). Neither N498S nor P598S are interpreted as resistance mutations based on EC50 ratio criteria (Tilloy et al., 2024). However, mutations conferring minor EC50 shifts can augment the level of resistance conferred by a coexisting mutation, as previously described (Chou, 2017; Chou et al., 2007). A786V confers no resistance despite the foscarnet and ganciclovir resistance attributed to adjacent finger domain mutations V787A/E/L (Andouard et al., 2016; Gilbert et al., 2011; Piret et al., 2019; Weinberg et al., 2003). Finally, A928V confers no EC50 shift, in contrast to the triple-drug resistance reported for A928T (Santos Bravo et al., 2022), a phenotype now revised to be concordant.

Re-testing of published phenotypes for the exonuclease domain III mutations D515E, D542E and A543V clarifies the correlation with phenotypes of other nearby mutations. D515E now has the same susceptible phenotype as published for D515G (Chou et al., 2003), and lacks the resistance phenotypes previously attributed to D515E (Fischer et al., 2015) and D515Y (Andouard et al., 2016; Cherrier et al., 2018). On the other hand, D542E and A543V both confer the characteristic ganciclovir-cidofovir cross-resistance of exonuclease domain mutations, unlike their previously published ganciclovir susceptibility (James et al., 2013; Santos Bravo et al., 2022). The A928T mutant was reported to have “high triple resistance” with EC50 ratio of >3 for cidofovir, ganciclovir and foscarnet (Santos Bravo et al., 2022), but showed no hint of resistance on our re-testing, the same finding as for A928V; there are no other nearby documented resistance mutations.

In conclusion, this study documents a new foscarnet resistance locus E949K/Q in the palm domain of the CMV UL54 polymerase gene, and revises some previously published phenotypes, all with the goal of increased reliability of genotypic CMV drug resistance testing. We encourage continued attention to rigor and reproducibility in phenotyping putative resistance mutations (Chou, 2020), including sequence verification, adequate assay replicates for high statistical confidence, technical quality controls (standardization of viral inocula, cell culture conditions and growth readouts) and consistent calibration of results to strains of known phenotype.

Highlights.

  1. Many unknown CMV UL54 mutations were detected in 2 large maribavir clinical trials

  2. Selected mutations were phenotyped for effects on drug susceptibility

  3. E949K/Q were newly shown to confer foscarnet resistance, with slower growth for E949K

  4. N498S and P598S showed minimally decreased antiviral susceptibility

  5. Published phenotypes of UL54 mutations D515E, D542E, A543V and A928T were revised

Acknowledgements

This work was supported by National Institutes of Health grant R01-AI116635 and use of Department of Veterans Affairs facilities and resources.

Footnotes

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CRediT author statement

Sunwen Chou: Conceptualization, Methodology, Validation, Investigation, Resources, Writing – Original Draft, Review & Editing, Supervision, Funding acquisition. Alexis Minyard and Justin Watanabe: Investigation, Validation, Writing – Review & Editing

Declaration of interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Sunwen Chou reports financial support was provided by National Institute of Allergy and Infectious Diseases. Corresponding author is editorial board member of Antiviral Research, with no role in the peer review or disposition of this manuscript. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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