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. 2019 Aug 19;55(6):739–768. doi: 10.1007/s11262-019-01700-z

Table 1.

Molecular markers/motifs in the hemagglutinin (HA; segment 4) gene of influenza virus experimentally verified molecular markers involved in AIV pathogenicity, receptor binding, replicative capacity, and transmission in both poultry and mammals

Mutation/motif Phenotype Subtypes tested References
H3 numberinga H5 numberingb
D101N D94N Increased virus binding to α2–6 H5N1 [200]
S126N S121N Increased virus binding to α2–6 H5N1 [201]
S137A S133A Increased pseudovirus binding to α2–6 H5N1 [44]
A138V A134V Increased infectivity in SIAT Cells H5N1 [202, 203]
G143R G139R Increased virus binding to α2–6 H5N1 [204]
S158N S154N Increased virus binding to α2–6 H5N1 [201]
N158D N154D Decreased virulence in mice H9N2 [205]
S159N S155N Increased virus binding to α2–6 H5N1 [201]
T160A T156A Increased virus binding to α2–6, increased transmission in guinea pigs H5N1 [201, 206]
G186V G182V Increased virus binding to α2–3 H7N9 [207]
N186K/D N182K/D Increased virus binding to α2–6 H5N1 [201, 203, 204, 206]
V186N V182N Increased binding to α2–6, decreased binding to α2–3 H13N6 [208]
P186L P182L Decreased binding to α2–3 H6N1 [209]
D187G D183G Increased virus binding to α2–6 H5N1 [47]
E190G E186G Increased virus binding to α2–6, maintained α2–3 binding, decreased virulence in mice H5N1 [47, 210]
E190V E186V Decreased binding to α2–3 and α2–6 H6N2 [211]
T190V T186V Enhances binding affinity to mammalian cells and replication in mammalian cells H9N2 [212]
T192I T188I Increased pseudovirus binding to α2–6 H5N1 [44]
K193R/T K189R/T Increased virus binding to α2–6 H5N1 [201, 213]
Q196R/H Q192R/H Increased virus binding to α2–6 H5N1 [47, 204, 214]
N197K N193K Increased virus binding to α2–6 H5N1 [204]
V214I V210I Increased virus binding to α2–6 H5N1 [214]
G225D G221D Increased virus binding to α2,6 H6N1 [43]
Q226L Q222L Increased virus binding to α2–6 H4N6 [50]
Increased virus binding to α2–6 H6N2 [211]
Increased virus binding to α2–6, decreased binding to α2–3 H5N1 [46]
Increased virus binding to α2–3, decreased binding to α2–6 H7N9 [52, 215]
Increased virus binding to α2–6, enhanced replication in mammalian cells and ferrets, enhanced contact transmission in ferrets H9N2 [49, 54]
Loss of binding to α2–3 H10N8 (human isolate) [53, 216, 217]
L226I L222I Decreased binding to α2–3 H7N9 [52]
S227N S223N Increased virus binding to α2–6 H5N1 [46, 47, 203, 218, 219]
G228A/S G224A/S Increased binding to α2–6, dual receptor specificity H4N6 [50]
G228S G224S Increased viral replication in mammalian cells and virulence in mice H1N2 [220]
Increased virus binding to α2–6 H5N1 [45, 46, 201, 209]
Decreased virus binding to α2–3 H6N2 [211]
Decreased binding to α2–3 and α2–6 receptors H7N9 [51]
Decreased binding to α2–3, no binding to α2–6 H10N8 (human isolate) [53, 217]
P239S P235S Increased virus binding to α2–6 H5N1 [214]
E255K E251K Increased virus binding to α2–6 H5N1 [47]
326 to 329 323 to 330 (R-X-R, K-R) Polybasic cleavage motif sequence required for high pathogenicity avian influenza viruses H5Nx [221–228]
H7Nx [229–231]
K387I K388I Decreased pH of fusion, increased HA stability, increased replication efficiency and virulence in mice H5N1 [130, 232, 233]
K393E K394E Increased pH of fusion, decreased HA stability, decreased virulence in mice H7N9 [234]
E83K, S128P E75K, S123P Increased virus binding to α2–6 H5N1 [204]
E83K, S128P, R496K E75K, S123P, R497K Increased virus binding to α2–6 H5N1 [204]
E83K, S128P, N197K, R496K E75K, S123P, N193K, R497K Increased virus binding to α2–6 H5N1 [204]
E83K, N197K E75K, N193K Increased virus binding to α2–6 H5N1 [204]
E83K, N197K, R496K E75K, N193K, R497K Increased virus binding to α2–6 H5N1 [204]
E83K, R496K E75K, R497K Increased virus binding to α2–6 H5N1 [204]
H110Y, T160A, Q226L, G228S H103Y, T156A, Q222L, G224S (with PB2: E627K; PB1: H99Y) Airborne transmissible in ferrets H5N1 [15, 58]
S114R, T115I S107R, T108I Increased virulence in chickens and mice, increased pH of fusion H5N1 [235]
S128P, N197K S123P, N193K Increased virus binding to α2–6 H5N1 [204]
S128P, N197K, R496K S123P, N193K, R497K Increased virus binding to α2–6 H5N1 [204]
S128P, R496K S123P, R497K Increased virus binding to α2–6 H5N1 [204]
∆c, A138V L129V, A134V Increased virus binding to α2–6 H5N1 [236]
∆, I155T L129del, I151T Increased virus binding to α2–6 H5N1 [214, 236]
S137A, T192I S133A, T188I Increased pseudovirus binding to α2–6 H5N1 [44]
G143R, N186K G139R, N182K Decreased binding to α2–3, increased virus binding to α2–6 H5N1 [46, 204]
N158D, N224K, Q226L, T318I N154D, N220K, Q222L, T315I Transmissible among ferrets H5N1 [14]
N158S, Q226L N154S, Q222L Increased virus binding to α2–6 H5N1 [237]
N158S, Q226L, N248D N154S, Q222L, N244D Increased virus binding to α2–6 H5N1 [237]
S159N, T160A S155N, T156A Increased virus binding to α2–6 H5N1 [201, 209]
S159N, T160A, S227N S155N, T156A, S223N Increased virus binding to α2–6, reduced lethality and systemic spread in mice H5N1 [238]
T160A, K193T, N224K, Q226L T156A, K189T, N220K, Q222L Increased virus binding to α2–6 H5N1 [213]
T160A, Q226L T156A, Q222L Increased virus binding to α2–6 H5N1 [201, 209]
T160A, Q226L, G228S T156A, Q222L, G224S Increased virus binding to α2–6 H5N1 [201, 209, 239]
T160A, S227N T156A, S223N Increased virus binding to α2–6 H5N1 [201, 209]
V186N, N228K V182N, N224K Increased virus binding to α2–6 H7N9 [51]
V186K/G, K193T, G228S V182 K/G, K189T, G224S Increased virus binding to α2–6 H7N9 [51]
V186N, N224K, G228S V182N, N220K, G224S Increased virus binding to α2–6 H7N9 [51]
N186K, Q196R, Q226L, S227N, G228S N182K, Q192R, Q222L, S223N, G224S Increased virus binding to α2–6 H5N1 [46]
N186K, Q226L, S227N, G228S N182K, Q222L, S223N, G224S Increased virus binding to α2–6 H5N1 [46]
N186K, Q226L, G228S N182K, Q222L, G224S Increased virus binding to α2–6 H5N1 [46]
E187G, E190D, K193S, Q226L, G228S E183G, E186D, K189S, Q222L, G224S Increased virus binding to α2–6 H5N1 [240]
E187G, Q226L,G228S E183G, Q222L,G224S Increased virus binding to α2–6 H5N1 [47]
D187G, S227N D183G, S223N Increased virus binding to α2–6 H5N1 [47]
T189A, G192R T185A, G188R Enhanced replication in ferrets, transmitted via aerosols among ferrets H9N2 (with human H3N2 backbone) [241]
E190G, Q226E, G228S E186G, Q222E, G224S Increased virus binding to α2–6 H5N1 [47]
K193T, G228S K189T, G224S Dual α2–3 and α2–6 binding H7N9 [51]
K193R, Q226L, G228S K189R, Q222L, G224S Increased virus binding to α2–6 H5N1 [239, 240]
Q196R, Q226L, S227N, G228S Q192R, Q222L, S223N, G224S Increased virus binding to α2–6 H5N1 [46]
Q196R, Q226L, G228S Q192R, Q222L, G224S Increased virus binding to α2–6 H5N1 [46, 47]
Q196R, S227N Q192R, S223N Increased virus binding to α2–6 H5N1 [46, 47]
N197K, R496K N193K, R497K Increased virus binding to α2–6 H5N1 [204]
K222Q, S227R K218Q, S223R Increased virus binding to α2–3 and α2–6 H5N1 [242]
N224K, G228S N220K, G224S Increased virus binding to α2–6 H7N9 [51]
Q226L, S227N, G228S Q222L, S223N, G224S Increased virus binding to α2–6 H5N1 [46]
Q226L, G228S Q222L, G224S Increased virus binding to α2–6 H4N6 [50]
Increased virus binding to α2–6; decreased antiviral response in host; reduced tissue tropism in guinea pigs H5N1 [45–47, 201, 206, 209, 215, 237, 239, 240, 243, 244]
Increased virus binding to α2–6 H7N7 (human isolate) [245]
Loss of binding to α2–3, no gain of binding to α2–6 H10N8 (human isolate) [53, 216, 217]

Single mutations are presented first followed by motifs involving multiple mutations. Individual markers and motifs are listed in numerical order for ease of identifying mutation of interest

aMutation/location H3 numbering relative to A/Aichi/2/1968 (H3N2)

bMutation/location H5 numbering relative to A/Vietnam/1203/2004 (H5N1)

c∆ indicates amino acids present in A/H5 but are deleted compared to A/H3