Table 1.
Fitness determinants of influenza A viruses.
| Segment | Amino Acid Position | Subtypes | Remarks | References |
|---|---|---|---|---|
| PB2 | E627K | H1N1, H3N2, H5N1 | Did not lead to enhanced virulence or transmission in pdm2009 H1N1, replicates more efficiently in mammalian cells before 2009, increased lethality in mice before 2009, increased H5N1 virulence in mice, increased H5N1 transmissibility in ferrets, determinant of cold sensitivity | [45,46,52,54,55,57,58,59,72] |
| T271A, 590S, 591R | H1N1 | Critical for viral replication and virulence of swine viruses in vitro and in vivo, associated with mammalian adaptation | [47,48,61] | |
| E667G | H1N1, H5N1 | Associated with mammalian adaptation, did not lead to enhanced virulence or transmission | [45,49] | |
| T588I | H1N1 | Increased polymerase activity and viral replication in mammalian cells, increased pathogenicity in mice, and regulated host antiviral innate immune responses in vitro and in vivo | [51] | |
| D701N | H1N1, H3N2, H5N1 | Did not lead to enhanced virulence or transmission in pdm2009 H1N, associated with mammalian adaptation, improved viral growth in mammalian cells, and enhanced aerosol transmission in guinea pigs of H3N2 and H5N1 | [45,46,61,62,63,64] | |
| 526R | H3N2, H5N1, H7N9 | Increased polymerase activity, in concert with 627K, enhanced replication and virulence in mice and was associated with mammalian adaptation | [65] | |
| E158G | H1N1 | Increased virulence in mice and increased polymerase activity in human cells | [66] | |
| I147T, K339T, A558T | H1N1, H5N1 | Increased replication in mammalian cells and enhanced virulence in mice | [67,68] | |
| V661A, A683T/A684S | H1N1 | Enhanced viral replication at 34 °C | [50] | |
| PB1 | V336I | H1N1 | Associated with mammalian adaptation | [71] |
| S216G | H1N1 | Associated with mammalian adaptation, attenuated virulence in mice, and reduced RdRp fidelity | [44,71] | |
| 473V | H5N1, H1N1 | Maintaining efficient viral replication | [72] | |
| L13P; S678N | H1N1 | Enhanced polymerase activity | [75] | |
| G622D | H5N1 | Decreased polymerase activity and attenuation in mice | [69] | |
| K577E | H9N2 | Increased pathogenicity in mice and was associated with mammalian adaptation | [77] | |
| M317I | H5N1 | Increased pathogenicity in mice | [78] | |
| N375S | H1N1, H2N2, H3N2 | Associated with mammalian adaptation | [79] | |
| K/I340; K/I649, T667 | H1N1 | Increased virulence in mice | [75,80] | |
| A469T | H1N1 | Enhanced polymerase activity, transmissibility in guinea pigs, and potential pathogenicity determinant | [81] | |
| N66S | H1N1, H5N1 | Increased pathogenicity in mice | [84] | |
| PA | T85I, G186S, L336M | H1N1 | Enhanced polymerase activity and enhanced morbidity in mice | [95] |
| V100I | H1N1 | Regulation of translation and accumulation of viral mRNA (in combination with T85I and G186S) | [96] | |
| A343T, K353R, T566A | H1N1 | Enhanced replication and virulence in mice | [97] | |
| K356R | H1N1 | Associated with mammalian adaptation | [71] | |
| T97I | H5N2 | Associated with mammalian adaptation | [98] | |
| V44I, V127A, C241Y, A343T, I573V | H5N1 | Increased replication in mammalian cells and enhanced virulence in mice were associated with mammalian adaptation | [99] | |
| K142Q | H5N1 | Enhanced replication and pathogenesis in mice when combined with PB2 627K, associated with mammalian adaptation | [101] | |
| V100I, N321K, I330V, A639T | H1N1 | Increased replication and pathogenesis in mice and increased disease severity and transmission in ferrets | [100] | |
| L295P | H1N1 | Increased polymerase activity in mice when combined with PB2 E158G/A | [102] | |
| HA | E391K | H1N1 | Currently, in pdm2009, viruses circulating potentially alter membrane fusion and antigenicity | [110] |
| 142N, 177N | H1N1 | Increased virulence and pathogenicity in mice, reduced sensitivity to neutralizing antibodies | [111,112] | |
| E190D, G225E | H1N1 | Increased receptor binding affinity, associated with mammalian adaptation | [11] | |
| D225G | H1N1 | Altered receptor binding specificity, increased replication, and transmissibility in ferrets | [106,107,108,109,112,113] | |
| NP | N319K | H7N7 | Associated with mammalian adaptation when combined with PB2 D701N | [64,114] |
| D375N | H1N1 | Increased virulence in mice, associated with mammalian adaptation | [4,26,115] | |
| 16D, 283P, 313Y, 357K | H1N1 | Circumvent antiviral MxA | [118,119] | |
| E53D, R100V, F313V | H1N1 | Increased resistance to MxA | [119] | |
| A336T, F346S, T378A | H1N1 | Adaptation to guinea pigs | [120,121,122] | |
| 319K | H5N1 | Greater virulence in mammals when combined with PA 615R | [76] | |
| N319K | H7N7 | Associated with mammalian adaptation when combined with PB2 D701N | [64,114] | |
| NA | H275Y, S246N, D198G, D198N, Y155H | H1N1 | Oseltamivir resistance | [44] |
| M | A86S | LAIV—H2N2 backbone, H3N2 | Increased viral replication in a temperature-dependent manner | [132] |
| A41P | H1N1 | Reduction in transmission efficiency | [133] | |
| A41V | H1N1 | Increased virulence in mice | [134,135] | |
| F79S | H1N1 | Attenuated replication | [136] | |
| R101S, R105S | H1N1 | Temperature-sensitive in vitro, attenuation in vivo | [137] | |
| 30D, 215A | H5N1 | Increased virulence in mice | [138] | |
| 30S, 207N, 209T | H1N1 | Viral morphology | [139] | |
| F62L; V166M | H1N1 | Enhanced replication and transmission in guinea pigs | [121,127] | |
| S31N, V27A, L26F, A30T | H1N1, H3N2 | Adamantane resistance | [143] | |
| L43T | H1N1 | Rimantadine resistance | [144] |