Mutation in Region III of the DNA Polymerase Gene Conferring Foscarnet Resistance in Cytomegalovirus Isolates from 3 Subjects Receiving Prolonged Antiviral Therapy

Chou, Sunwen; Marousek, Gail I.; Parenti, D. M.; Gordon, Shelly M.; Lavoy, A. G.; Ross, J. G.; Miner, Richard C.; Drew, W. Lawrence

doi:10.1086/515648

Cited by 72 publications

(38 citation statements)

References 10 publications

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“…The domain III amino terminus of herpesviruses consists of a DNA template binding region (47), immediately followed by residues important for pyrophosphate binding and nucleotide incorporation (9,15,44). Mutation A834P is situated within a putative ␣-helical region (␣ helix Q) at the less well defined carboxy end of DNA polymerase domain III (32,45), where two other CMV mutations (T838A and G841A) and a herpes simplex virus (HSV) mutation (R842S) associated with antiviral resistance have been identified (22,26,42).…”

Section: Discussionmentioning

confidence: 99%

Multidrug Resistance Conferred by Novel DNA Polymerase Mutations in Human Cytomegalovirus Isolates

Scott

Weinberg

Rawlinson

et al. 2007

Antimicrob Agents Chemother

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The emergence of antiviral-resistant cytomegalovirus (CMV) strains is a continuing clinical problem, with increased numbers of immunocompromised patients given longer-duration antiviral prophylaxis. Two previously unrecognized CMV DNA polymerase mutations (N408K and A834P) identified separately and together in at-risk lung and kidney transplant recipients and a third mutation (L737M) identified in a liver transplant recipient were characterized by marker transfer to antiviral-sensitive laboratory strains AD169 and Towne. Subsequent phenotypic analyses of recombinant strains demonstrated the ability of mutation N408K to confer ganciclovir (GCV) and cidofovir (CDV) resistance and of mutation A834P to confer GCV, foscarnet, and CDV resistance. Mutation L737M did not confer resistance to any of the antiviral agents tested. A recombinant strain containing both N408K and A834P demonstrated increased GCV and CDV resistance compared to the levels of resistance of the virus containing only the A834P mutation. The addition of mutation N408K in combination with A834P also partially reconstituted the replication impairment of recombinant virus containing only A834P. This suggests that perturbation of both DNA polymerization (A834P) and exonuclease (N408K) activities contributes to antiviral resistance and altered replication kinetics in these mutant strains. The identification of these multidrug-resistant CMV strains in at-risk seronegative recipients of organs from seropositive donors suggests that improved prophylactic and treatment strategies are required. The additive effect of multiple mutations on antiviral susceptibility suggests that increasing antiviral-resistant phenotypes can result from different virus-antiviral interactions.

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Section: Discussionmentioning

confidence: 99%

Multidrug Resistance Conferred by Novel DNA Polymerase Mutations in Human Cytomegalovirus Isolates

Scott

Weinberg

Rawlinson

et al. 2007

Antimicrob Agents Chemother

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“…17 Resistance to foscarnet, to cidofovir, and multiple resistance have been described. [25][26][27][28] No previous reports have described systemic therapy for CMV refractory to all three standard drugs.…”

Section: Discussionmentioning

confidence: 99%

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

Avery

Bolwell

Yen‐Lieberman

et al. 2004

Bone Marrow Transplant

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“…Derived sequences of each isolate were aligned with the strain AD169 reference sequence with a sequence text editor. Amino acid differences were tabulated and compared with previously published pol resistance mutations (5,17,32).…”

Section: Methodsmentioning

confidence: 99%

How Evolution of Mutations Conferring Drug Resistance Affects Viral Dynamics and Clinical Outcomes of Cytomegalovirus-Infected Hematopoietic Cell Transplant Recipients

Springer

Chou

et al. 2005

J Clin Microbiol

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Infection with cytomegalovirus (CMV) remains a significant cause of morbidity and mortality among hematopoietic cell transplant (HCT) recipients. We describe two pediatric HCT recipients who developed persistent and severe drug-resistant CMV infections. CMV resistance to foscarnet and ganciclovir was detected after only 6 and 11 weeks of therapy, respectively. Viral pol mutations associated with drug resistance in these patients included T838A (a novel mutation) and D588N, which were shown by marker transfer to confer foscarnet and multidrug resistance, respectively. Each of these mutations significantly reduced in vitro replication of CMV, suggesting that they may decrease viral fitness. This finding was further supported by the disappearance of mutations upon withdrawal of antiviral pressure in one patient. Novel antivirals or combination therapy may be required for the treatment of drug-resistant CMV in HCT recipients and perhaps in other severely immunocompromised patients.

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Mutation in Region III of the DNA Polymerase Gene Conferring Foscarnet Resistance in Cytomegalovirus Isolates from 3 Subjects Receiving Prolonged Antiviral Therapy

Cited by 72 publications

References 10 publications

Multidrug Resistance Conferred by Novel DNA Polymerase Mutations in Human Cytomegalovirus Isolates

Multidrug Resistance Conferred by Novel DNA Polymerase Mutations in Human Cytomegalovirus Isolates

Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection

How Evolution of Mutations Conferring Drug Resistance Affects Viral Dynamics and Clinical Outcomes of Cytomegalovirus-Infected Hematopoietic Cell Transplant Recipients

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