A natural variant in ANP32B impairs influenza virus replication in human cells

J Gen Virol. 2021 Sep;102(9):001664. doi: 10.1099/jgv.0.001664.


Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wild-type ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wild-type ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wild-type ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.

Keywords: ANP32B; Influenza virus; dominant negative; polymerase dimer; single nucleotide variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Influenza A Virus, H3N2 Subtype / enzymology
  • Influenza A Virus, H3N2 Subtype / physiology*
  • Models, Molecular
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Polymorphism, Single Nucleotide*
  • Protein Conformation
  • Protein Multimerization
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / metabolism*
  • Virus Replication


  • ANP32A protein, human
  • ANP32B protein, human
  • Nuclear Proteins
  • Protein Subunits
  • RNA-Binding Proteins
  • RNA-Dependent RNA Polymerase