Cytomegalovirus UL97 mutations associated with ganciclovir resistance in immunocompromised patients from Argentina

Puch, Silvia Sánchez; Ochoa, Claudia; Carballal, Guadalupe; Zala, Carlos; Cahn, Pedro; Brunet, Rosario; Salomón, Horacio; Videla, Cristina

doi:10.1016/j.jcv.2003.11.003

Cited by 14 publications

(14 citation statements)

References 22 publications

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“…Approximately 95% of GCV‐resistant HCMV strains contain one or more mutations (amino acid substitutions or deletions) in UL97 . Typically, amino acid substitutions or short (1‐ to 17‐amino acid) in‐frame deletions located within the ATP binding site and/or the phosphate transfer site alter the ability of pUL97 to phosphorylate GCV .…”

Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

“…Nevertheless, there are some amino acid positions where single‐base modifications change from natural polymorphism to resistance mutation: K599R has been assessed as a polymorphism , while K599T was reported to induce GCV resistance ; and V466G, but not V466M, confers resistance to GCV . Furthermore, some natural polymorphisms may modulate the drug resistance level when combined with other mutations . Indeed, some authors suggest that D605E mutation could partially or totally compensate the effect of the GCV resistance, conferred by M460V or A594P .…”

Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

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Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Campos

Ribeiro

Boutolleau

et al. 2016

Reviews in Medical Virology

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Human cytomegalovirus (HCMV) infection is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant recipients. The significant clinical impact of HCMV infection and progression to HCMV disease among allogeneic hematopoietic stem cell transplant recipients has been reduced by prophylactic, preemptive, and curative treatments using ganciclovir, valganciclovir, foscarnet, and cidofovir. Resistance to (val)ganciclovir results from mutations localized in HCMV UL97 gene (encoding the pUL97 phosphotransferase), UL54 gene (encoding the pUL54 DNA polymerase), or both genes, whereas foscarnet and cidofovir resistance results from mutations localized within UL54 gene only. This review is focused on HCMV antiviral drug resistance, including the functions of target genes of antivirals, the mechanisms of antiviral resistance, the different mutations in pUL97 and pUL54 that have been identified in either clinical isolates or laboratory strains, and their impact on HCMV susceptibility to antiviral drugs. It emphasizes the importance of proving that observed genetic changes confer resistance so they can be distinguished from polymorphisms. Because of the emergence of HCMV resistance to currently available drugs, novel drugs are urgently needed for the therapeutic management of HCMV-resistant infections in hematopoietic stem cell transplant patients.

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Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Campos

Ribeiro

Boutolleau

et al. 2016

Reviews in Medical Virology

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“…However, these analyses sample only a small fraction of the genome (11,15). Moreover, in the presence of selective pressure, mutations have been identified in both human and murine cytomegalovirus (HCMV and MCMV, respectively) (5,7,17). For example, in HCMV, mutations in UL97 account for ganciclovir (GCV) resistance in up to 25% of immunosuppressed patients infected with HCMV (12,18).…”

mentioning

confidence: 99%

Stability of Murine Cytomegalovirus Genome after In Vitro and In Vivo Passage

Cheng¹,

Valentine

Gao³

et al. 2010

J Virol

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While large DNA viruses are thought to have low mutation rates, only a small fraction of their genomes have been analyzed at the single-nucleotide level. Here, we defined the genetic stability of murine cytomegalovirus (MCMV) by whole-genome sequencing. Independently assembled sequences of three sister plaques showed only two single-base-pair substitutions after in vitro passage. In vivo-passaged MCMV likewise demonstrated low mutation rates, comparable to those after in vitro passage, indicating high genome stability of MCMV at the single-nucleotide level in the absence of obvious selection pressure.Large DNA viruses, such as herpesviruses, are thought to have low mutation rates as estimated by methods such as analysis of restriction fragment length polymorphisms or function of individual genes (10,16). However, these analyses sample only a small fraction of the genome (11,15). Moreover, in the presence of selective pressure, mutations have been identified in both human and murine cytomegalovirus (HCMV and MCMV, respectively) (5, 7, 17). For example, in HCMV, mutations in UL97 account for ganciclovir (GCV) resistance in up to 25% of immunosuppressed patients infected with HCMV (12, 18). However, whether these resistant mutant strains arise de novo or represent new infection is impossible to ascertain in the clinical setting.Previous studies demonstrated that after in vivo passage, MCMV does acquire de novo mutations. Mutants emerge after passage through mice lacking adaptive immunity but carrying the Cmv1 r allele, which encodes the Ly49H activation receptor on NK cells (7,19). The only known ligand for Ly49H is MCMVencoded open reading frame (ORF) m157. In mice infected with a plaque-purified MCMV clone containing intact m157, all escape viruses had m157 mutations. These mutants carried either single-amino-acid substitutions or premature stop codons and demonstrated increased virulence in naïve Cmv1 r mice (8). In contrast, there were no mutations in the adjacent ORFs, m156 and m158. Taken together, these data indicate that mutations occur in both HCMV and MCMV under selective pressure. However, absent this pressure, their genomewide stability has not been determined at the single-nucleotide level.In the current study, we set out to detail MCMV genomewide sequence changes after in vitro and in vivo passages in the absence of obvious selection pressure. To determine MCMV genome stability in vitro, we subcloned our laboratory stock of Smith strain MCMV (a gift from Herbert Virgin, Washington University, St. Louis, MO) that had been previously passaged in vivo. Our stock was plaque purified twice on NIH-3T12 monolayers. At the second round of plaque purification, three sister plaques were selected and independently amplified in vitro by sequential passages for 21 days in NIH-3T12 cells. Virions were then isolated from the culture medium, and genomic DNA was extracted for shotgun sequencing by the Sanger method. Using the bioinformatics software package Phred/Phrap/Consed (9), we then independently assembled compl...

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“…Without appropriate immune reconstitution, life-long treatment is required to prevent reactivation of CMV disease [50]. Primary and secondary treatment failures have been associated with the development of resistence mutations in the UL54/UL97 genes [174][175][176][177][178][179][180]. Therapy for severe or vision-threatening CMV retinitis includes high-dose intravenous treatment (7.5-15 mg/kg/day in three divided doses) with ganciclovir for 2-3 weeks or until there is a definitive clinical response followed by a life-long maintenance therapy of 5-6 mg/kg/ day for 5-7 days if there is no immune recovery [181].…”

Section: Therapy Of CMV End-organ Disease In Hiv Infectionmentioning

confidence: 99%

Treatment and Prevention of Cytomegalovirus-Associated Diseases in HIV-1 Infection in the Era of HAART

Schmidt

Bollmann

2010

HIV Ther.

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Cytomegalovirus (CMV) infection is one of the most common chronic viral infections and is one of the most important opportunistic infections in HIV-infected patients. Although HAART has substantially improved the morbidity and mortality of HIV-infected patients and decreased the frequencies of AIDS-related diseases, opportunistic infections including CMV end-organ diseases still remain a significant clinical challenge. Here we review the clinical manifestation and diagnosis of CMV end-organ diseases including the potential role of CMV infection in the pathogenesis of cardiovascular disease. We explain how HAART has changed the epidemiology of CMV disease in HIV infection and discuss how this influences current treatment guidelines for the prevention of CMV disease and CMV-associated immune recovery syndrome.

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Cytomegalovirus UL97 mutations associated with ganciclovir resistance in immunocompromised patients from Argentina

Cited by 14 publications

References 22 publications

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Stability of Murine Cytomegalovirus Genome after In Vitro and In Vivo Passage

Treatment and Prevention of Cytomegalovirus-Associated Diseases in HIV-1 Infection in the Era of HAART

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