Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022

Details

• Alternative Title:
  Antiviral Res
• Personal Author:
  Nguyen, Ha T. ; Chesnokov, Anton ; Cruz, Juan De La ; Pascua, Philippe Noriel Q. ; Mishin, Vasiliy P. ; Jang, Yunho ; Jones, Joyce ; Di, Han ; Ivashchenko, Andrei A. ; Killian, Mary Lea ; Torchetti, Mia K. ; Lantz, Kristina ; Wentworth, David E. ; Davis, Charles T. ; Ivachtchenko, Alexandre V. ; Gubareva, Larisa V.
• Description:
  Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A(H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1,015 sequences of HPAI A(H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4b A(H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors, baloxavir and the investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A(H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.
• Subjects:
  Animals Antiviral Agents Birds Drug Resistance, Viral Enzyme Inhibitors Influenza A Virus, H5N1 Subtype Influenza In Birds Mammals Neuraminidase Oseltamivir United States

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• Keywords:
  Antiviral Resistance AV5080 Baloxavir CEN Inhibitor Neuraminidase Inhibitors
• Source:
  Antiviral Res. 217:105679
• Pubmed ID:
  37494978
• Pubmed Central ID:
  PMC10508830
• Document Type:
  Journal Article
• Funding:
  CC999999/ImCDC/Intramural CDC HHSUnited States/
• Volume:
  217
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:a54fe5972a1f441ad192e8db8d695845dc291def9595ce96c4ff028eeac2556d2e73b0b3986a7e06bd7406a592f6e58e28dafc6ecc9203de1058c0d72e9716fd
• Download URL:
  https://stacks.cdc.gov/view/cdc/133268/cdc_133268_DS1.pdf
• File Type:
  [PDF - 89.66 KB ]