Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus.
Zanamivir, a neuraminidase inhibitor, has shown promise as a drug to control influenza. During prolonged treatment with zanamivir, a mutant virus was isolated from an immunocompromised child infected with influenza B virus. A hemagglutinin mutation (198 Thr-->Ile) reduced the virus affinity for receptors found on susceptible human cells. A mutation in the neuraminidase active site (152 Arg-->Lys) led to a 1000-fold reduction in the enzyme sensitivity to zanamivir. When tested in ferrets, the mutant virus had less virulence than the parent; however, it had a growth preference over the parent in zanamivir-treated animals. Despite these changes, the sensitivity of the mutant virus to zanamivir assessed by a standard test in MDCK cells was unaffected. These data indicate that the current methods for monitoring resistant mutants are potentially flawed because no tissue culture system adequately reflects the receptor specificity of human respiratory tract epithelium.
Department of Internal Medicine, University of Virginia, Charlottesville, USA.
L V
LV
Gubareva
M N
MN
Matrosovich
M K
MK
Brenner
R C
RC
Bethell
R G
RG
Webster
D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000276:immunology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004285:Dogs; D004352:Drug Resistance, Microbial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005289:Ferrets; D006146:Guanidines; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D007223:Infant; D009981:Influenza B virus / Q000235:genetics / Q000276:immunology; D007251:Influenza, Human / Q000150:complications / Q000188:drug therapy*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications / Q000276:immunology / Q000628:therapy; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D011714:Pyrans; D012367:RNA, Viral / Q000032:analysis; D011991:Receptors, Virus / Q000187:drug effects / Q000235:genetics*; D012794:Sialic Acids / Q000627:therapeutic use*; D014709:Vero Cells; D053243:Zanamivir
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012367:RNA, Viral; D011991:Receptors, Virus; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir