SUMMARY
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 serve essential but redundant roles to support influenza virus polymerase activity. 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 variant results in a D130A substitution in ANP32B, which is less able to support influenza virus polymerase (FluPol) activity than wildtype ANP32B. Using a split luciferase binding assay, we also show reduced interaction between ANP32B-D130A and FluPol. We then use CRISPR/Cas9 genome editing to generate the mutant homozygous genotype in human eHAP cells, and show that FluPol activity and virus replication are attenuated in cells expressing wildtype ANP32A and mutant ANP32B-D130A. This is in contrast to cells that completely lack expression of ANP32B where no attenuation is seen. We conclude that ANP32B-D130A exerts a dominant negative effect on the pro-viral activity of ANP32A in cells, and suggest that carriers of rs182096718 may have some genetic protection against influenza viruses.