Giuseppe
Emeritus
Detection E119V and E119I Mutations in Influenza A (H3N2) Viruses Isolated from an Immunocompromised Patient: Challenges in Diagnosis of Oseltamivir-Resistance. (Antimicrob Agents Chemoter., abstract, edited)
30. Antimicrob Agents Chemother. 2010 Mar 1. [Epub ahead of print]
Detection E119V and E119I Mutations in Influenza A (H3N2) Viruses Isolated from an Immunocompromised Patient: Challenges in Diagnosis of Oseltamivir-Resistance.
Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV. - Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta GA, USA; Departments of Pediatrics and Pathology, Baylor College of Medicine and Diagnostic Virology Laboratory, Texas Children's Hospital, Houston, Texas, USA.
The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay ( approximately 60-fold increase in IC50 compared to a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays ( approximately 50- and 350-fold increases in IC50, respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA (E119V/I). Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and investigative NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients is previously reported; however, the E119I detected here is a novel mutation which reduces susceptibility to several NAIs. Neither mutation was not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multi-drug resistant influenza viruses in oseltamivir-treated immunocompromised subjects, and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
PMID: 20194700 [PubMed - as supplied by publisher]
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30. Antimicrob Agents Chemother. 2010 Mar 1. [Epub ahead of print]
Detection E119V and E119I Mutations in Influenza A (H3N2) Viruses Isolated from an Immunocompromised Patient: Challenges in Diagnosis of Oseltamivir-Resistance.
Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, Gubareva LV. - Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta GA, USA; Departments of Pediatrics and Pathology, Baylor College of Medicine and Diagnostic Virology Laboratory, Texas Children's Hospital, Houston, Texas, USA.
The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay ( approximately 60-fold increase in IC50 compared to a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays ( approximately 50- and 350-fold increases in IC50, respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA (E119V/I). Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and investigative NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients is previously reported; however, the E119I detected here is a novel mutation which reduces susceptibility to several NAIs. Neither mutation was not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multi-drug resistant influenza viruses in oseltamivir-treated immunocompromised subjects, and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.
PMID: 20194700 [PubMed - as supplied by publisher]
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