PT  - JOURNAL ARTICLE
AU  - Rute Maria Pinto
AU  - Siddharth Bakshi
AU  - Spyros Lytras
AU  - Mohammad Khalid Zakaria
AU  - Simon Swingler
AU  - Julie C Worrell
AU  - Vanessa Herder
AU  - Margus Varjak
AU  - Natalia Cameron-Ruiz
AU  - Mila Collados Rodriguez
AU  - Mariana Varela
AU  - Arthur Wickenhagen
AU  - Colin Loney
AU  - Yanlong Pei
AU  - Joseph Hughes
AU  - Elise Valette
AU  - Matthew L Turnbull
AU  - Wilhelm Furnon
AU  - Kerrie E Hargrave
AU  - Quan Gu
AU  - Lauren Orr
AU  - Aislynn Taggart
AU  - Chris Boutell
AU  - Finn Grey
AU  - Edward Hutchinson
AU  - Paul Digard
AU  - Isabella Monne
AU  - Sarah K Wootton
AU  - Megan K L MacLeod
AU  - Sam J Wilson
AU  - Massimo Palmarini
TI  - Zoonotic avian influenza viruses evade human BTN3A3 restriction
AID  - 10.1101/2022.06.14.496196
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.14.496196
4099  - http://biorxiv.org/content/early/2022/06/15/2022.06.14.496196.short
4100  - http://biorxiv.org/content/early/2022/06/15/2022.06.14.496196.full
AB  - Cross-species transmission of avian influenza A viruses (IAVs) into humans could represent the first step of a future pandemic1. Multiple factors limiting the spillover and adaptation of avian IAVs in humans have been identified, but they are not sufficient to explain which virus lineages are more likely to cross the species barrier1,2. Here, we identified human BTN3A33 (butyrophilin subfamily 3 member A3) as a potent inhibitor of avian but not human IAVs. We determined that BTN3A3 is constitutively expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts at the early stages of virus replication by inhibiting avian IAV vRNA transcription. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F, or rarely 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, several serotypes of avian IAVs that spilled over into humans in recent decades evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure4. Importantly, we identified more than 150 avian IAV lineages with a BTN3A3-resistant genotype. In conclusion, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.Competing Interest StatementThe authors have declared no competing interest.