Comprehensive Screening for Naturally Occurring Hepatitis C Virus Resistance to Direct-Acting Antivirals in the NS3, NS5A, and NS5B Genes in Worldwide Isolates of Viral Genotypes 1 to 6
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
HCV data sets.
Naturally occurring polymorphism at positions associated with resistance to DAA (natural RAVs).
Amino acid signature patterns of resistance to DAA for HCV genotypes 1 to 6.
Searching for natural multiple resistance to different DAA classes.
Calculation of the genetic barrier.
Evolutionary history of naturally occurring RAVs.
RESULTS
Frequency of natural RAVs in HCV genotypes 1 to 6.
NS3 position | Amino acid variant(s) (no. of isolates) for genotypea: | ||||||
---|---|---|---|---|---|---|---|
GT1a (n = 1,482) | GT1b (n = 992) | GT2 (n = 135) | GT3 (n = 117) | GT4 (64) | GT5 (n = 37) | GT6 (n = 74) | |
C16S | C (1,476), S (1), T (1) | C (984), T (2), S (1), Y (1) | A (111), T (18), S (4), P (2) | T (117) | T (64) | A (37) | T (74) |
V36A/M/L/G/I/C | V (1,450), L (21), M (7), I (1) | V (978), L (8), I (3) | L (134), M (1) | L (117) | L (64) | L (37) | V (57), L (14), I (3) |
A39V | A (1,461), T (8), G (7), S (3), V (1) | A (979), T (4), S (1) | V (134), I (1) | A (102), T (10), S (5) | A (60), T (4) | A (37) | A (72), T (1), D (1) |
Q41R/K/P/H | Q (1,467), H (12) | Q (988), H (2) | Q (135) | Q (116) | Q (64) | Q (36), H (1) | Q (74) |
F43S/C/Y/V/I/L | F (1,481), Y (1) | F (992) | F (135) | F (117) | F (63) | F (36) | F (74) |
I48V | I (1,443), V (33) | I (382), V (597), L (4), F (2), T (1) | I (132), V (3) | I (15), V (98), L (4) | I (25), V (39) | I (37) | I (42), V (28), L (4) |
T54A/S/V/G/C | T (1,446), S (34) | T (966), S (23) | T (133), A (1) | T (117) | T (59), S (2) | T (37) | T (73) |
V55A/F/I/K/T | V (1,410), I (36), A (32) | V (984), I (3), A (2) | V (134), G (1) | V (116), I (1) | V (64) | V (36), L (1) | V (73) |
D79E | D (1,478), E (2), N (1) | D (990), N (2) | D (1), E (133), K (1) | D (112), E (4), N (1) | D (64) | D (37) | D (71), E (3) |
Q80K/L/N/R/H/G | Q (884), K (542), L (28), R (9), N (7), S (1), M (1) | Q (948), L (33), R (5), K (4) | G (135) | Q (116), R (1) | Q (63) | K (37) | Q (55), K (18), L (1) |
A87T | A (1,435), S (22), T (7), C (5), I (1) | A (969), S (13), P (2), T (2), M (1), E (1) | A (1), S (127), T (3), N (3), G (1) | A (114), S (3) | A (56), S (5), C (1), V (1) | S (35), T (2) | A (54), S (19), T (1) |
Y105C | Y (1,476), F (3) | Y (976), F (11) | Y (135) | Y (117) | Y (30), F (34) | Y (37) | Y (70), F (3), C (1) |
R109K | R (1,482) | R (986), M (1), K (1) | R (135) | R (117) | R (63) | R (37) | R (73) |
R117H | R (1,448), C (19), H (10), S (2), L (1) | R (929), H (30), C (28), Q (1), F (1) | R (135) | R (117) | R (64) | R (37) | R (74) |
S122G/A/R/N/T | S (1,365), G (96), N (11), T (2), C (2) | S (798), G (94), T (56), N (35), C (2) | R (110), K (23), T (1) | S (117) | S (5), T (55), N (4) | S (2), T (31), A (4) | S (13), T (36), N (25) |
R123H/K | R (1,477), K (3) | R (983), K (8) | R (135) | T (117) | R (61), K (1) | R (34), H (1) | R (74) |
I132V | I (1,466), V (5), L (2) | I (282), V (692), L (10) | I (7), L (127) | I (8), L (109) | I (59), L (4), V (1) | I (35), L (1), V (1) | I (51), L (22) |
S138T/D/P | S (1,479) | S (988), F (1) | S (135) | S (117) | S (63), F (1) | S (37) | S (71), F (1) |
R155K/T/I/M/G/L/S/Q/P/N/W | R (1,463), K (13) | R (991), P (1) | R (135) | R (115), K (2) | R (63) | R (36) | R (73) |
A156S/T/V/I/F/N/G/D | A (1,478) | A (992) | A (134) | A (117) | A (64) | A (37) | A (73), V (1) |
V158I/M | V (1,480) | V (990), I (1) | V (130), I (3), M (2) | V (115), A (1), I (1) | V (62), L (1), I (1) | V (33), M (2), L (1) | V (71), I (2) |
V163L | V (1,478) | V (984), I (4) | V (133), I (1), A (1) | V (114), E (1) | V (62) | V (36), A (1) | V (74) |
D168Q/A/Y/V/E/T/N/P/I/H/G/F/S/K | D (1,471), E (3), G (1) | D (979), E (9) | D (135) | Q (116) | D (64) | D (19), E (18) | D (72), E (2) |
V170A/T/G/L/M | V (55), I (1,422), T (1) | V (682), I (307), T (1) | V (2), I (133) | V (11), I (105) | V (63), I (1) | V (3), I (33) | V (50), I (23), A (1) |
E173G | E (1,481) | E (992) | E (133), D (1), G (1) | E (116), D (1) | E (63) | E (36) | E (74) |
S174F/P | S (584), N (827), G (59), D (2), A (1), C (1) | S (960), A (19), F (6), T (4), H (1), L (1), C (1) | S (106), T (18), A (11) | S (3), T (106), A (7), I (1) | S (59), A (3) | S (4), N (32) | S (27), N (44), A (2), G (1) |
M175L | L (1,476) | M (977), L (14) | L (134), I (1) | L (117) | L (64) | L (37) | M (74) |
E176G | E (1,466), G (7), D (4), A (1), S (1) | E (986), Q (2), D (1), G (1) | D (110), A (17), N (8) | S (93), N (18), A (5), H (1) | E (62), A (1) | E (37) | E (46), Q (26), D (2) |
NS5a position | Amino acid variant(s) (no. of isolates) for genotypea: | ||||||
---|---|---|---|---|---|---|---|
GT1a (n = 861) | GT1b (n = 810) | GT2 (n = 149) | GT3 (n = 226) | GT4 (n = 60) | GT5 (n = 14) | GT6 (n = 96) | |
Reference GT1b (Con1) | |||||||
Q24L | Q (2), K (844), R (5), E (4), S (1) | Q (788), K (11), R (10) | S (113), T (35), A (1) | S (218), L (5), A (1), G (1), T (1) | K (60) | Q (14) | K (65), Q (29), R (2) |
L28M/V | L (1), M (824), V (28), T (6), I (2) | L (789), M (16), V (3), P (1) | L (90), F (56), C (3) | L (1), M (223), I (2) | L (48), M (9), V (2), I (1) | L (14) | L (22), V (42), F (11), T (11), A (5), M (3), G (1) |
R30Q/L | R (4), Q (840), H (14), L (2) | R (756), Q (39), K (7), L (3), M (2), H (1) | R (5), K (143) | R (2), A (180), K (30), T (6), L (3), S (2), V (2), M (1) | R (32), L (17), S (4), T (4), Q (2), A (1) | Q (14) | R (3 1), S (41), A (22), N (1) |
L31M/V/F | L (853), M (8) | L (766), M (37), I (3), V (1), F (1), P (1) | L (28), M (121) | L (208), M (15), V (2) | L (7), M (53) | L (14) | L (95), I (1) |
P32L | P (860) | P 810 | P (149) | P (226) | P (70) | P (14) | P (96) |
Q54H/N/L/Y | H (847), Y (11), C (1), F (1) | Q (524), H (253), N (9), L (6), Y (15), C (1), E (1), T (1) | T (147), N (1), S (1) | S (196), T (29) | H (60) | S (13), Y (1) | H (69), R (10), Y (7), T (3), C (2), N (2), S (1) |
P58S/A/L/T/H | P (23), H (823), R (6), Y (6), Q (1), C (1), D (1) | P (750), S (30), T (10), L (7), Q (6), A (6) | P (141), S (6), H (1), T (1) | P (215), S (8), R (1), A (1), T (1) | P (52), T (6), R (1) | P (14) | P (44), T (39), G (5), S (4), A (2), L (1) |
Q62E/R/A/P/S | E (830), D (24), G (3), A (1) | Q (774), E (16), R (6), H (5), N (2), K (2), S (1), D (1), G (1), L (1) | N (128), A (6), S (4), T (4), V (3), H (1), I (1), E (1) | Q (1), S (135), T (46), M (7), D (7), L (6), E (6), V (5), A (4), P (4), I (4), N (1) | Q (4), E (42), S (4), N (4), D (3), R (2), V (1) | T (13), A (1) | Q (4), V (34), D (15), N (11), T (8), A (8), S (5), M (4), E (3), H (1), I (1), R (1), K (1) |
A92T | A (854), P (7) | A (783), T (16), V (7), G (1) | A (1), C (142), S (6) | E (224), G (1) | A (57), T (1) | A (14) | A (96), P (1) |
Y93H/N/C | Y (849), H (5), C (4), N (1), F (1) | Y (769), H (39), C (2) | Y (148), F (1) | Y (219), H (7) | Y (55), H (2), T (1), R (1), S (1) | T (14) | T (79), S (14), I (2) |
F149L | F (858), L (1) | F (809) | F (149) | F (226) | F (58), L (1), S (1) | F (14) | F (96) |
V153M/L/I | V (15), L (834), I (4), P (1) | V (657), L (147), I (5), T (1) | V (149) | V (197), L (28) | V (57), L (1) | L (14) | V (92), I (4) |
M202L | M (856), L (2), Q (2), I (1) | M (807), L (3) | M (148), V (1) | M (225), L (1) | M (60) | M (14) | M (94), L (2) |
M265V/T | M (858), V (2), L (1) | M (791), K (9), V (5), T (1), W (1) | M (148), L (1) | M (222), V (2), I (1), L (1) | M (13) | M (14) | M (57), V (32), L (3), A (2), I (1) |
D320E | D (857), E (2), N (1), G (1) | D (796), E (6), S (3), N (2) | D (131), E (7), N (4), S (3), G (2), Q (1) | D (226) | D (43), E (11), A (4), S (1) | D (14) | D (94), N (1), G (1) |
Y321N | Y (856) | Y (805), H (1) | Y (147) | Y (226) | Y (58) | Y (14) | Y (95), N (1) |
Reference GT1a (H77) | |||||||
L23F | L (856), M (1) | L (807), P (2), I (1) | L (149) | L (220), P (5), I (1) | L (57) | L (14) | L (96) |
M28T | M (824), V (28), T (6), I (2), L (1) | M (16), L (789), V (3), P (1) | L (90), F (56), C (3) | M (223), I (2), L (1) | M (9), L (48), V (2), I (1) | L (14) | M (3), V (42), L (22), F (11), T (11), A (5), G (1) |
Q30H/R/E | Q (840), H (14), R (4), L (2) | Q (39), R (755), K (7), L (3), M (2), H (1) | K (143), R (5) | A (180), K (30), T (6), L (3), V (2), S (2), R (2), M (1) | Q (2), R (32), L (17), S (4), T (4), A (1) | Q (14) | S (41), R (31), A (22), N (1) |
L31V/M | L (853), M (8) | L (766), M (37), I (3), V (1), F (1), P (1) | L (28), M (121) | L (208), M (15), V (2) | L (7), M (53) | L (14) | L (95), I (1) |
P32L | P (860) | P (810) | P (149) | P (226) | P (60) | P (14) | P (96) |
H58D/P | H (823), P (23), R (6), Y (6), Q (1), D (1), C (1) | P (750), S (30), T (10), L (7), Q (6), A (6) | H (1), P (141), S (6), T (1) | P (215), S (8), R (1), A (1), T (1) | P (52), T (6), R (1) | P (14) | P (44), T (39), G (5), S (4), A (2), L (1) |
Y93N/C | Y (849), H (5), C (4), N (1), F (1) | Y (769), H (39), C (2) | Y (148), F (1) | Y (219), H (7) | Y (55), H (2), T (1), R (1), S (1) | T (14) | T (79), S (14), I (2) |
D320E | D (857), E (2), N (1), G (1) | D (796), E (6), S (3), N (2) | D (131), E (7), N (4), S (3), G (2), Q (1) | D (226) | D (43), E (11), A (4), S (1) | D (14) | D (94), N (1), G (1) |
NS5B NI resistance position | Amino acid variant(s) (no. of isolates) for genotypea: | ||||||
---|---|---|---|---|---|---|---|
GT1a (n = 581) | GT1b (n = 417) | GT2 (n = 122) | GT3 (n = 81) | GT4 (n = 62) | GT5 (n = 8) | GT6 (n = 73) | |
A15G | A (562), S (14), T (3), V (2) | A (379), S (32), T (3), V (2), G (1) | A (4), G (80), S (32), C (2), R (1), I (1) | A (2), S (75), T (2), N (2) | A (62) | S (8) | A (71), V (2) |
K72M | K (579), M (1) | K (416), N (1) | K (122) | K (80), R (1) | K (61) | K (6), R (2) | K (72) |
S96T | S (581) | S (417) | S (122) | S (81) | S (62) | S (8) | S (73) |
N142T | N (581) | N (385), S (29), T (1) | N (120), T (2) | N (78), S (3) | N (58), S (3), T (1) | N (8) | N (73) |
L159F | L (581) | L (397), F (19) | L (122) | L (81) | L (62) | L (8) | L (72) |
R222Q | R (579), D (1) | R (417) | R (122) | R (81) | R (62) | R (8) | R (65), K (5), S (3) |
C223H/Y | C (581) | C (416), R (10) | C (121), W (1) | C (81) | C (62) | C (8) | C (73) |
I239V/L | I (580), V (1) | I (416) | I (120), L (2) | I (78), V (3) | I (10), V (52) | I (8) | I (62), V (10) |
S282T/R | S (580), R (1) | S (416), T (1) | S (122) | S (79), R (1) | S (61), T (1) | S (8) | S (73) |
A300T | Q (296), R (260), K (21), L (4) | A (18), S (300), T (95), V (1), R (1), F (1) | L (105), R (8), Q (8), K (1) | T (67), S (6), K (5), M (2), R (1) | T (46), S (8), V (5), N (1), M (1) | L (8) | A (1), Q (53), E (5), K (4), M (3), S (3), T (2), N 1 |
L320I/F | L (579) | L (415), R (1) | L (122) | L (80), Q (1) | L (61) | L (8) | L (73) |
V321I | V (580), I (1) | V (414), I (3) | V (120), F (1), I (1) | V (81) | V (59), I (3) | V (8) | V (73) |
A396G | A (579) | A (417) | A (122) | A (81) | A (61), V (1) | A (8) | A (73) |
Y586C | Y (544), C (2) | Y (399), N (1), F (1), C (1) | F (114), L (2), V (1) | F (57), V (1) | F (49) | F (7) | F (71), I (1) |
NS5B NNI resistance position | Amino acid variant(s) (no. of isolates) for genotypea: | ||||||
---|---|---|---|---|---|---|---|
GT1a (n = 581) | GT1b (n = 417) | GT2 (n = 122) | GT3 (n = 81) | GT4 (n = 62) | GT5 (n = 8) | GT6 (n = 73) | |
T19S/P | Q (574), E (5), D (1), P (1) | T (43), S (368), N (7), G (1) | E (118), G (2), D (1), R (1) | E (81) | T (17), S (37), A (4), P (3), N (1) | E (8) | E (73) |
K50R | K (576), R (5) | K (403), R (12), Q (1) | K (122) | K (78), R (3) | K (61) | K (8) | K (69), R (4) |
D55E | D (578), E (3) | D (517) | D (122) | D (81) | D (62) | D (8) | D (68), E (2), H (1), G (1) |
M71V | V (578), I (2), A (1) | M (393), I (13), V (10), L (1) | V (75), I (47) | V (71), I (9) | I (59), T (1), V (1) | M (8) | M (3), V (18), I (45), T (6) |
H95Q/R | H (575) | H (414), L (1), Q (1) | H (122) | H (78), N (2), K (1) | H (62) | H (8) | H (71), C (1), R (1) |
V138I | V (1), I (579), L (1) | V (27), I (390) | V (10), I (111), A (1) | V (1), I (80) | I (62) | I (8) | V (2), I (70) |
L314F | L (577), P (1), F (1) | L (417) | L (122) | L (81) | L (62) | L (8) | L (73) |
C316Y/F/N/S | C (580) | C (287), N (126), H (1), R (1), Y (1), S (1) | C (121), W (1) | C (79), G (2) | C (54), N (5), H (3) | C (8) | C (73) |
A338V | A (579) | A (31), V (386) | A (96), V (24), T (1) | A (75), V (5), T (1) | A (58), V (3), T (1) | A (8) | A (70), V (1) |
I363V | I (578), V (1) | I (416), V (1) | I (122) | I (81) | I (62) | V (8) | I (73) |
S365T/A/L/O/F | S (579) | S (416), A (1) | S (122) | S (81) | S (62) | S (8) | S (73) |
S368A/T | S (577) | S (416), P (1) | S (122) | S (81) | S (62) | S (8) | S (70), A (1) |
T389S/A | T (572), A (3), S (2), M (1), V (1) | T (400), A (9), I (4), S (2), M (2) | T (119), A (1), I (1), S (1) | T (58), E (22), D (1) | E (62) | Q (8) | T (52), V (13), I (5), L (1), S (1), A (1) |
L392I | L (568), F (11), I (3) | L (396), I (16), F (4) | L (35), I (85), F (1) | L (81) | L (62) | L (8) | L (71), I (1) |
N411S | N (578) | N (417) | N (120), T (2) | N (79), S (2) | N (62) | N (8) | N (73) |
M414L/T/I/V/Q | M (577), L (1), V (1) | M (415), L (1), I (1) | Q (119), L (3) | M (81) | L (28), V (23), I (10), Q (1) | M (8) | M (71), A (1) |
L419M/V/S/I | L (578) | L (411), I (5) | L (2), I (117), V (3) | L (3), I (78) | I (61) | L (8) | L (1), I (72) |
A421V | A (505), V (73), M (1) | A (396), V (21) | A (23), V (98) | A (1), V (80) | A (5), V (57) | A (5), V (3) | A (1), V (72) |
R422K | R (576), K (3) | R (417) | R (122) | R (81) | R (62) | R (8) | R (73) |
M423T/V/I/A | M (561), I (13), V (3), T (1), A (1) | M (423) | M (122) | M (79), I (2) | M (62) | I (8) | M (73) |
I424V | I (560), V (19) | I (381), V (35) | V (122) | V (81) | I (16), V (54) | V (8) | I (1), V (72) |
M426T/V/I | M (531), L (41), F (1), T (1), I (1) | M (405), L (10), A (1), T (1) | M (120), L (2) | M (75), L (4), V (1), I (1) | M (61) | T (1) | M (63), C (10) |
A442T | A (579) | A (405), T (10), V (2) | N (101), D (19), S (2) | A (23), P (54), S (4) | A (62) | A (7), T (1) | A (49), V (19), P (3) |
C445F | C (573), G (1), Y (1) | C (411), F (4), W (1) | F (122) | F (81) | F (62) | F (8) | F (73) |
I447F | I (578), F (1) | I (447) | M (118), L (4) | M (81) | M (62) | M (8) | I (39), M (32), L (1) |
Y448H/C | Y (579) | Y (416), C (1) | Y (122) | Y (81) | Y (62) | Y (8) | Y (73) |
C451R | C (572), Y (4), H (2), W (1) | C (333), T (46), Y (13), H (7), I (7), N (3), S (3), V (2), R (1) | V (120), A (1), I (1) | T (80), V (1) | T (62) | V (8) | T (73) |
Y452H | Y (577), H (2) | Y (410), H (7) | Y (122) | Y (81) | Y (62) | Y (8) | Y (72), H (1) |
C455F | E (567), Q (6), K (5) | E (412), Q (4), G (1) | C (1), N (87), S (30), T (4) | T (81) | T (62) | T (8) | C (1), T (43), S (24), N (3), A (2) |
M/I462T | I (578), L (1) | I (416), V (1) | I (119), V (3) | I (80) | I (62) | R (8) | I (72), V (1) |
R465G | R (575), K (1) | R (416), L (1) | R (122) | R (80) | R (58), K (4) | R (8) | R (73) |
I482L/V/T/S | I (564), L (1) | I (411), L (1) | L (119) | L (75) | L (60) | I (8) | L (72) |
A486V/I/T/M | A (563), D (1) | A (411) | A (119) | A (73), S (2) | A (55), S (1) | A (7), S (19) | A (34), G (38) |
V494A/I | V (562), I (1) | V (411), A (1) | A (119) | C (56), I (14), A (3), S (2) | V (56), A (2) | V (8) | V (14), A (57), M (1) |
P495L/A/S/T/Q | P (564) | P (412) | P (119) | P (75) | P (57) | P (8) | P (71), L (1) |
P496A/T/S | P (563) | P (412) | P (118), S (1) | P (75) | P (58) | P (8) | P (72) |
V499A | V (4), A (545), T (15) | V (364), A (41), T (6), I (1) | V (9), A (106), T (3), M (1) | V (1), A (74) | V (1), A (57) | A (8) | A (72) |
R531K | R (467), K (84) | R (275), K (136) | R (15), K (102) | R (59) | K (53) | K (8) | R (32), K (40) |
G554D/S | G (548) | G (402), D (1) | G (109), S (9) | G (57), S (2) | G (52) | G (8) | G (72) |
Y555C | Y (548) | Y (411) | A (111), S (7) | V (51), I (4), A (3), G (1) | A (44), S (4), G (3) | A (8) | Y (34), G (19), F (17), V (1) |
S556G/N/C | S (543), G (4), N (1) | S (373), G (30), N (6), D (1) | G (117), C (1) | S (1), G (58) | G (49), N (2), A (1) | G (8) | S (41), D (18), R (11), G (2) |
G558R | G (548) | G (405) | G (114), S (4) | G (3), N (55), S (1) | G (51), E (1) | G (8) | G (70), A (1), V (1) |
D559G/S/N | D (548) | D (403), N (1) | D (117), H (1) | D (59) | D (52) | D (8) | D (71), G (1) |
W571R | W (545), R (2) | W (402), L (1), R (1) | L (101), S (6), F (4), Y (3), I (3) | H (39), Y (16), L (1), Q (1) | Y (49), F (1), H (1) | Y (5), N (1), C (1) | M (24), L (21), I (12), T (6), V (3), F (3), N (1) |
Amino acid signature patterns and RAVs.
NS3 position | Amino acid for sequence or genotypea: | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Con1 reference (1b) | GT1 consensus amino acid | All GT1 | 1a | 1b | 2 | 3 | 4 | 5 | 6 | |
C16S | C | C | • | • | • | A | T* | T* | A* | T* |
V36A/M/L/G/I/C | V | V | • | • | • | L | L* | L* | L* | • |
A39V | A | A | • | • | • | V | • | • | • | • |
Q41R/K/P/H | Q | Q | • | • | • | • | • | • | • | • |
F43S/C/Y/V/I/L | F | F | • | • | • | • | • | • | • | • |
I48V | V | I | I | I | • | I | • | • | I | I |
T54A/S/V/G/C | T | T | • | • | • | • | • | • | • | • |
V55A/F/I/K/T | V | V | • | • | • | • | • | • | • | • |
D79E | D | D | • | • | • | E | • | • | • | • |
Q80K/L/N/R/H/G | Q | Q | • | • | • | G* | • | • | K* | • |
A87T | A | A | • | • | • | S | • | • | S | • |
Y105C | Y | Y | • | • | • | • | • | F | • | • |
R109K | R | R | • | • | • | • | • | • | • | • |
R117H | R | R | • | • | • | • | • | • | • | • |
S122G/A/R/N/T | S | S | • | • | • | R | • | T | T | T (<50%) |
R123H/K | R | R | • | • | • | • | T* | • | • | • |
I132V | V | I | I | I | • | L | L | I | I | I |
S138T/D/P | S | S | • | • | • | • | • | • | • | • |
R155K/T/I/M/G/L/S/Q/P/N/W | R | R | • | • | • | • | • | • | • | • |
A156S/T/V/I/F/N/G/D | A | A | • | • | • | • | • | • | • | • |
V158I/M | V | V | • | • | • | • | • | • | • | • |
V163L | V | V | • | • | • | • | • | • | • | • |
D168Q/A/Y/V/E/T/N/P/I/H/G/F/S/K | D | D | • | • | • | • | Q*? | • | • | • |
V170A/T/G/L/M | V | I | I | I | • | I | I | • | I | • |
E173G | E | E | • | • | • | • | • | • | • | • |
S174F/P | S | S | • | N | • | • | T | • | N | N |
M175L | M | L | L | L*? | • | L | L* | L* | L* | • |
E176G | E | E | • | • | • | D | S | • | • | • |
NS5a position | Amino acid for sequence or genotypea: | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Con1 reference (1b) | GT1 consensus amino acid | All GT1 | 1a | 1b | 2 | 3 | 4 | 5 | 6 | |
L23F | L | L | • | • | • | • | • | • | • | • |
Q24L | Q | K | K | K | • | S | S | K* | • | K |
L28M/T | L | M | M | M | • | • | M | • | • | V (<50%) |
R30Q/L | R | Q | Q | Q | • | K | A | • | Q | S (<50%) |
L31M/V/F | L | L | • | • | • | M | • | M | • | • |
P32L | P | P | • | • | • | • | • | • | • | • |
Q54H/N/L/Y | Q | H | H | H | • | T | S | H* | S | H |
P58S/A/L/T/H/D/P | P | H | H | H (49.5%) | H | • | • | • | • | • |
Q62E/R/A/P/S | Q | E | E | E | • | N | S | E | T | V |
A92T | A | A | • | • | • | C | E | • | • | • |
Y93H/N/C | Y | Y | • | • | • | • | • | • | T* | T |
F149L | F | F | • | • | • | • | • | • | • | • |
V153M/L/I | V | L | L | L | • | • | • | • | L | • |
M202L | M | M | • | • | • | • | • | • | • | • |
M265V/T | M | M | • | • | • | • | • | • | • | • |
D320E | D | D | • | • | • | • | • | • | G* | • |
Y321N | Y | Y | • | • | • | • | • | • | • | • |
NS5B NI resistance position | Amino acid for sequence or genotypea: | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Con1 reference (1b) | GT1 consensus amino acid | All GT1 | 1a | 1b | 2 | 3 | 4 | 5 | 6 | |
A15G | A | A | • | • | • | G | S | • | S* | • |
K72M | K | K | • | • | • | • | • | • | • | • |
S96T | S | S | • | • | • | • | • | • | • | • |
N142T | N | N | • | • | • | • | • | • | • | • |
L159F | L | L | • | • | • | • | • | • | • | • |
R222Q | R | R | • | • | • | • | • | • | • | • |
C223H/Y | C | C | • | • | • | • | • | • | • | • |
I239V/L | I | I | • | • | • | • | • | V | • | • |
S282T/R | S | S | • | • | • | • | • | • | • | • |
A300T | A | S (<30%) | S (<30%) | Q | S | L | T | T | L* | Q |
L320F/I | L | L | • | • | • | • | • | • | • | • |
V321I | V | V | • | • | • | • | • | • | • | • |
A396G | A | A | • | • | • | • | • | • | • | • |
Y586C | Y | Y | • | • | • | F | F | F*# | F*# | F |
NS5B NNI resistance position | Amino acid for sequence or genotypea: | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Con1 reference (1b) | GT1 consensus amino acid | All GT1 | 1a | 1b | 2 | 3 | 4 | 5 | 6 | |
T19S/P | T | Q | Q | Q | S | E | E* | S | E* | E* |
K50R | K | K | • | • | • | • | • | • | • | • |
D55E | D | D | • | • | • | • | • | • | • | • |
M71V | M | V | V | V | • | V | V | I | • | I |
H95Q/R | H | H | • | • | • | • | • | • | • | • |
138I | I | I | • | • | • | • | • | • | • | • |
L314F | L | L | • | • | • | • | • | • | • | • |
C316Y/F/N/S | C | C | • | • | • | • | • | • | • | • |
A338V | A | A | • | • | V | • | • | • | • | • |
I363V | I | I | • | • | • | • | • | • | V* | • |
S365T/A/L/O/F | S | S | • | • | • | • | • | • | • | • |
S368A/T | S | S | • | • | • | • | • | • | • | • |
T389S/A | T | T | • | • | • | • | • | E* | Q* | • |
L392I | L | L | • | • | • | I | • | • | • | • |
N411S | N | N | • | • | • | • | • | • | • | • |
M414L/T/I/V/Q | M | M | • | • | • | Q | • | L | • | • |
L419M/V/S/I | L | L | • | • | • | I | I | I*? | • | I |
A421V | A | A | • | • | • | V | V | V | • | V |
R422K | R | R | • | • | • | • | • | • | • | • |
M423T/V/I/A | M | M | • | • | • | • | • | • | I* | • |
I424V | I | I | • | • | • | V* | V* | V | V* | V |
M426T/V/I | M | M | • | • | • | • | • | • | • | • |
A442T | A | A | • | • | • | N | P | • | • | • |
C445F | C | C | • | • | • | F* | F* | F* | F* | F* |
I447F | I | I | • | • | • | M | M* | M* | M* | • |
Y448H/C | Y | Y | • | • | • | • | • | • | • | • |
C451R | C | C | • | • | • | V | T | T* | V* | T* |
Y452H | Y | Y | • | • | • | • | • | • | • | • |
C455F | E | E | • | • | • | N | T* | T* | T* | T |
M/I462T | I | I | • | • | • | • | • | • | • | • |
R465G | R | R | • | • | • | • | • | • | • | • |
I482L/V/T/S | I | I | • | • | • | L*# | L*# | L*# | • | L*# |
A486V/I/T/M | A | A | • | • | • | • | • | • | • | G |
V494A/I | V | V | • | • | • | A*# | C | • | • | A |
P495L/A/S/T/Q | P | P | • | • | • | • | • | • | • | • |
P496A/T/S | P | P | • | • | • | • | • | • | • | • |
V499A | V | A | A | A | • | A | A | A | A | A*# |
R531K | R | R | • | • | • | K | • | K*# | K* | K |
G554D/S | G | G | • | • | • | • | • | • | • | • |
Y555C | Y | Y | • | • | • | A | V | A | A* | • |
S556G/N/C | S | S | • | • | • | G | G | G | G* | • |
G558R | G | G | • | • | • | • | N | • | • | • |
D559G/S/N | D | D | • | • | • | • | • | • | • | • |
W571R | W | W | • | • | • | L | H | Y | Y | M (<50%) |
Haplotypes with multiple RAVs to different DAA classes.
Genetic barriers.
Evolutionary history of natural RAVs.

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