Mutations in Retroviral Genes Associated with Drug Resistance
Jennifer Hammond,1 Brendan A. Larder,2 Raymond F. Schinazi 3 and John W. Mellors1
1 University of Pittsburgh, 603 Parran Hall, Pittsburgh, PA 15261.
2 Virco, UK, 162A Cambridge Science Park, Milton Road, Cambridge CB4 4GH.
3 Emory University/VAMC, 1670 Clairmont Road, Decatur, GA 30033.
Introduction
Drug resistance is the inevitable consequence of incomplete suppression of HIV replication. The rapid replication rate of HIV and its inherent genetic variation have led to the identification of many HIV variants that exhibit altered drug susceptibility. The growing number of drug resistance mutations listed in this revised table stands as a testimony to the genetic flexibility of HIV. This updated table lists 143 mutations occurring in the HIV Gag (3), Protease (44), Reverse Transcriptase (69), or Envelope (27) genes. Although the tables are quite comprehensive, the reader should be reminded that the mutations described are predominantly found in clade B virus and not in other HIV genotypes. The revised table includes for the first time drug resistance mutations that have been identified for SIV and FIV.
In the table the phrase "Enzyme resist." refers to inhibition assays done just with a mutated enzyme. Instead of introducing the mutations into a virus and testing the susceptibility of the mutant virus to a drug, researchers introduce the mutation(s) into the enzyme and determine their effect by running enzyme activity assays. These sort of assays don't take into account changes in other viral proteins (like gag) that would also help confer resistance, which is the reason for distinguishing enzyme resistance from whole virus resistance.
Acknowledgments
The authors would like to gratefully acknowledge their colleagues for assistance in assembling this table. This work was supported in part by the National Institutes of Health, the Department of Veterans Affairs, and the Georgia VA Research Center for AIDS and HIV Infections.
Mutations in HIV RT that confer drug resistance, ordered by position.
Amino Acid Codon Class of Drug Compound In In -Fold Cross-resistace comments Refs
Change channge vitro Vivo -resistance (-fold)
M 41 L ATG to TTG/CTG Nucleoside RTI AZT ? Y 4 - M41L/T215Y: 60-70-fold; (1, 2, 3)
M41L/D67N/K70R/T215Y: 180-fold.
A 62 V GCC to GTC Multiple Nucleoside Resistance N Y Nil - A62V alone has no effect, but in (4, 5)
combination with mutations at 75,
77, 116, 151 causes multi NRTI
resistance.
K 65 R AAA to AGA Nucleoside RTI ddI Y Y 4-10 ddC; PMEA; 3TC(5) Infrequently observed in patients (6)
receiving ddI or ddC
K 65 R AAA to AGA Nucleoside RTI ddC Y Y 4-10 - - (6, 7)
K 65 R AAA to AGA Nucleoside RTI 1592U89 Y N 3 - K65R/L74V: 3.6-fold; K65R/M184V: (8)
7-fold; K65R/L74V/M184V: 10.2-fold
K 65 R AAA to AGA Nucleoside RTI DXG Y ? 8 other dioxolane Reverses AZT resistance in (9)
derivatives D67N/K70R/T215Y/K219Q background
K 65 R AAA to AGA Nucleoside RTI PMEA Y N 10-25 - - (10, 11)
K 65 R AAA to AGA Nucleoside RTI PMPA Y ? 3.5 - - (12)
D 67 N GAC to AAC Nucleoside RTI AZT Y Y - - D67N/K70R/T215Y/K219Q: 120-fold; (1, 2, 3)
M41L/D67N/K70R/T215Y: 180-fold.
T 69 D ACT to GAT Nucleoside RTI ddC N Y 5 - - (13)
K 70 E AAA to GAA Nucleoside RTI PMEA Y Y 9 3TC (7); PFA: 2-fold - (14, 15)
hypersusceptibility
K 70 R AAA to AGA Nucleoside RTI AZT Y Y - - D67N/K70R/T215Y/K219Q: (1, 2, 3)
120-fold
L 74 I TTA to ATA HIV-1 Specific RTI HBY 097 Y ? - - - (16)
L 74 V TTA to GTA Nucleoside RTI ddI N Y 5-10 ddC(4) Can reverse effect of T215Y (17)
AZT resistance mutation
L 74 V TTA to GTA Nucleoside RTI 1592U89 Y N 4 - K65R/L74V: 3.6-fold; (8)
K65R/L74V/M184V: 10.2-fold
L 74 V TTA to GTA Nucleoside RTI DXG Y ? 4 - - (9)
L 74 V TTA to GTA HIV-1 Specific RTI HBY 097 Y ? - - - (16)
V 75 I GTA to TTA HIV-1 Specific RTI HBY 097 Y ? - - Compensates for negative effect
of G190E mutation on RT activity (16)
V 75 I GTA to ATA Multiple Nucleoside Resistance - N Y Nil - V75I alone has no effect, but in (4, 5)
combination with mutations at 62,
77, 116, 151 causes multi NRTI
resistance.
V 75 L GTA to ATA HIV-1 Specific RTI HBY 097 Y ? - - - (16)
V 75 T GTA to ACA Nucleoside RTI d4T Y Y 7 ddI; ddC; d4C; Observed with d4T selection in vitro, (18, 19)
(-)-FTC rarely in patients receiving d4T
F 77 L TTC to CTC Multiple Nucleoside Resistance - N Y Nil - F77L alone has no effect, but in (4, 5)
combination with mutations at 62,
75, 116, 151 causes multi NRTI
resistance.
W 88 G TGG to GGG Pyrophosphate Analogue RTI Foscarnet (PFA) Y Y 5 Hypersusceptibility Observed after selection with AZT (20, 21, 22)
to AZT and PFA; suppresses effects of AZT
mutations
W 88 S TGG to TCG Pyrophosphate Analogue RTI Foscarnet (PFA) N Y 2-4 Wild-type suscep- Partially suppresses effects (20, 21, 22)
-tibility to AZT.
E 89 G GAA to GGA Pyrophosphate Analogue RTI Foscarnet (PFA) Y N 14 - Isolated by screening RT clones for (23)
ddGTP resistance
E 89 K GAA to GGA Pyrophosphate Analogue RTI Foscarnet (PFA) Y N >16 - Suppresses effects of AZT resistance (21, 22)
mutations
L 92 I TTA to ATA Pyrophosphate Analogue RTI Foscarnet (PFA) Y N 8 - Partially suppresses effects of AZT (21, 22)
resistance mutations
A 98 G GCA to GGA HIV-1 Specific RTI L-697,661 N Y 8 - - (24)
A 98 G GCA to GGA HIV-1 Specific RTI Nevirapine N Y - - - (25)
L 100 I TTA to ATA HIV-1 Specific RTI TIBO R82150 Y ? >100 - suppresses effects of AZT resistance (26, 27, 28)
mutations
L 100 I TTA to ATA HIV-1 Specific RTI TIBO R82913 Y ? - - Found in combination with E138K (29)
L 100 I TTA to ATA HIV-1 Specific RTI L-697,661 Y N 2 - - (24)
L 100 I TTA to ATA HIV-1 Specific RTI Nevirapine N Y - - - (30)
L 100 I TTA to ATA HIV-1 Specific RTI DMP 266 (L-743,726) Y ? 8-11 - Combinations of mutations needed for (31, 32)
high-level resistance; L100I/V108I:
1,000-fold; L100I/V179D/Y181C:
1,000-fold
L 100 I TTA to ATA HIV-1 Specific RTI BHAP U-88204E Y ? - - - (33, 34)
L 100 I TTA to ATA HIV-1 Specific RTI UC-68 (638532) Y ? 70 - - (35)
L 100 I TTA to ATA HIV-1 Specific RTI UC-70 (638534) Y ? 758 - - (36)
L 100 I TTA to ATA HIV-1 Specific RTI UC-781 Y ? 20 - Activity of UC-781 versus L100I, (37, 38)
K103N, V106A, E138K, Y181C and Y188L
reduced by 2-, 7-, 1.5-, 1.5-, 5- and
150-fold, respectively, compared to
wild type
L 100 I TTA to ATA HIV-1 Specific RTI UC-84 (615985) Y ? >40, > 33 - - (36, 39)
K 101 E AAA to GAA HIV-1 Specific RTI 8-Chloro-TIBO R091767 ? Y - - - (40)
K 101 E AAA to GAA HIV-1 Specific RTI BHAP U-87201E (atevirdine) N Y - - K101E, Y188H, E233Y and K238T observed
with U-87201E/AZT combination therapy (41)
K 101 E AAA to GAA HIV-1 Specific RTI DMP 266 (L-743,726) Y ? 1,000 - - (32)
K 101 E AAA to GAA HIV-1 Specific RTI L-697,661 N Y 8 - - (24)
K 101 E AAA to GAA HIV-1 Specific RTI UC-10 (645129) Y ? 12 - K101E/Y181C: 200-fold (36, 42, 43)
K 101 E AAA to GAA HIV-1 Specific RTI UC-38 (629243) Y N - - K101E/G190E: >100-fold (36)
K 101 E AAA to GAA HIV-1 Specific RTI UC-57 (647014) Y ? - - K101E/Y181C: 58-fold (36)
K 101 E AAA to GAA HIV-1 Specific RTI UC781 Y ? 7 UC040(18);Nevirapine(15) V108I/ Y181C: 55-fold;
K101E/ V108I/ Y181C: 500-fold. (37, 43)
K 101 I AAA to ATA HIV-1 Specific RTI UC-16 Y N 10 - K101I/G141E: 10-fold (36)
K 101 Q AAA to CAA HIV-1 Specific RTI Trovirdine Y ? - - Found in combination with V108I (44, 45)
K 103 N AAA to AAC HIV-1 Specific RTI 8-Chloro-TIBO R091767 ? Y - - - (40)
K 103 N AAA to AAC HIV-1 Specific RTI BHAP U-87201E (atevirdine) N Y - - K103N and Y181C observed with (41)
monotherapy
K 103 N AAA to AAC HIV-1 Specific RTI BHAP U-90152 (delavirdine) ? Y - - K103N/Y181C seen separately and in (46)
combination in patients
K 103 N AAA to AAC HIV-1 Specific RTI DMP 266 (L-743,726) Y Y 67 - Predominant mutation in vivo (31)
K 103 N AAA to AAC HIV-1 Specific RTI L-697,593 Y ? 20 - K103N/Y181C: > 1,000-fold (47)
K 103 N AAA to AAC HIV-1 Specific RTI L-697,661 Y Y 8 - K103N and Y181C most common with (24, 48)
monotherapy
K 103 N AAA to AAC HIV-1 Specific RTI Loviride (R89439, Ï-APA) Y Y - - - (49)
K 103 N AAA to AAC HIV-1 Specific RTI MKC442 (I-EBU) Y ? - - predominant mutation in vivo (50)
K 103 N AAA to AAC HIV-1 Specific RTI Nevirapine N Y - - - (30)
K 103 N AAA to AAC HIV-1 Specific RTI TIBO R82913 Y ? >100 - K103N/Y181C: > 1,000-fold (33)
K 103 N AAA to AAC HIV-1 Specific RTI UC-10 (645129) Y N 5 - - (35)
K 103 N AAA to AAC HIV-1 Specific RTI UC-81 (615727) Y ? 40 - -
K 103 Q AAA to CAA HIV-1 Specific RTI L-697,661 N Y 8 - - (48)
K 103 R AAA to AGA HIV-1 Specific RTI Trovirdine Y ? - Nevirapine; 9-chloro-TIBO K103R/V179D: 500-fold; Found (44, 45)
in combination with V179D or
Y181C
K 103 R AAA to AGA HIV-1 Specific RTI MKC442(1-EBU) Y Y - - - (51)
K 103 T AAA to ACA HIV-1 Specific RTI BHAP U-90152 (delavirdine) ? Y - - - (46)
K 103 T AAA to ACA HIV-1 Specific RTI UC-42 Y N 100 - - (36)
V 106 A GTA to GCA HIV-1 Specific RTI BHAP U-88204E Y ? - - - (34)
V 106 A GTA to GCA HIV-1 Specific RTI E-EBU-dM Y ? - - - (52)
V 106 A GTA to GCA HIV-1 Specific RTI Nevirapine Y Y ~100 - No effect on AZT resistance (25, 29, 30, 33)
V 106 A GTA to GCA HIV-1 Specific RTI TIBO R82913 Y ? ~100 - - (29)
V 106 A GTA to GCA HIV-1 Specific RTI UC-69 (646989) Y ? - - V106A/V181C: 166-fold (36)
V 106 A GTA to GCA HIV-1 Specific RTI UC-82 Y ? 13 - Activity of UC-82 versus L100I, (37, 38)
K103N, V106A, E138K, Y181C and
Y188L reduced by 2-, 6-, 1.5-,
2-, 4- and 200-fold, respectively,
compared to wild type
V 106 A GTA to GCA HIV-1 Specific RTI S-2720 (Quinoxaline) Y ? - - P225H follows V106A. Also seen (53)
with L101I and Y181C. Double and
triple mutants highly resistant to
other NNRTI's, including MKC442
V 106 I GTA to ATA HIV-1 Specific RTI HBY 097 - - - - Appears under lowered drug (54)
concentration selection
V 108 I GTA to ATA HIV-1 Specific RTI DMP 266 (L-743,726) Y ? - - L100I/V108I: 1,000-fold (31)
V 108 I GTA to GCA HIV-1 Specific RTI L-697,661 Y Y 4 - - (24)
V 108 I GTA to ATA HIV-1 Specific RTI Loviride (R89439, Ï-APA) Y ? - - - (49)
V 108 I GTA to GCA HIV-1 Specific RTI MKC442 (I-EBU) Y ? - - - (50)
V 108 I GTA to ATA HIV-1 Specific RTI Nevirapine N Y - - - (30)
V 108 I GTT to GAT HIV-1 Specific RTI TIBO R82913 N Y >100 R82150 (> 100) - (55)
V 108 I GTA to ATA HIV-1 Specific RTI Trovirdine Y ? - - Found in combination with K101Q (44, 45)
V 108 I GTA tO ATA HIV-1 Specific RTI UC781 Y ? - - V108I/Y181C: 55 fold. K101E/V108I (43)
/Y181C: 500 fold.
Y 115 F TAT to TTT Nucleoside RTI 1592U89 Y N 2 - K65R/L74V and/or Y115F with M184V: (8)
10 fold; L74V/Y115F/M184V: 11-fold
F 116 Y TTT to TAT Multiple Nucleoside Resistance - N Y Nil - F116Y alone has no effect, but in (4, 5)
combination with mutations at 62,
75, 77, 151 causes multi NRTI
resistance.
P 119 S CCC to TCC Nucleoside RTI F-ddA Y ? 4 - Found with V179D and/or L214F, (56)
which are possibly compensatory
E 138 K GAG to AAG HIV-1 Specific RTI TSAO Y ? >100 - E138A (GAG to GCG) in TSAO-naive (57, 58, 59)
patients confers TSAO viral
resistance
E 138 K GAG to AAG HIV-1 Specific RTI MKC442 (I-EBU) Y N - - Obtained in the concomitant presence (60)
of low 3TC concentrations
E 138 K GAG to AAG HIV-1 Specific RTI TIBO R82913 Y ? - - Found in combination with L100I (27)
E 138 K GAG to AAG HIV-1 Specific RTI UC-82 Y ? 5 - Activity of UC-82 versus L100I, (37, 38)
K103N, V106A, E138K, Y181C and Y188L
reduced by 2-, 6-, 1.5-, 2-, 4- and
200-fold, respectively, compared to
wild type
E 138 K GAG to AAG HIV-1 Specific RTI UC-84 (615985) Y ? >100 TSAOs - (35, 61)
T 139 I ACA to ATA HIV-1 Specific RTI Calanolide A Y ? >70 Not other NNRTIs - (39)
G 141 E GGG to GAG HIV-1 Specific RTI UC-16 Y N - - K101I/G141E: 10-fold (35)
Q 151 M CAG to ATG Multiple Nucleoside Resistance - N Y AZT: 10; ddI/ ddC: 5 - Pivotal multi nucleoside RTI (4, 5, 62)
resistance mutation (first to occur),
found in association with
combinations of four other mutations:
A62V/ V75I/ F77L/ F116Y/Q151M: AZT
190-fold; ddI 50-fold; ddC 20-fold;
d4T > 10-fold
S 156 A TCA to GCA Pyrophosphate Analogue RTI Foscarnet (PFA) Y N 4.5 - - (21)
Q 161 L CAA to CTA Pyrophosphate Analogue RTI Foscarnet (PFA) Y Y 5 - Q161L/H208Y: 9-fold; Q161L/H208Y (20)
suppresses effects of AZT mutations
V 179 D GTT to GAT HIV-1 Specific RTI DMP 266 (L-743,726) Y ? - - L100I/V179D/Y181C: 1,000-fold (31)
V 179 D GTT to GAT HIV-1 Specific RTI L-697,661 N Y 4 - - (24)
V 179 D GTT to GAT HIV-1 Specific RTI TIBO R82913 N Y 20 R82150 (20) - (63)
V 179 D GTT to GAT HIV-1 Specific RTI Trovirdine Y ? - - Found in combination with K103R or (44, 45)
Y181C; V179D/Y181C: > 1,000-fold
V 179 D GTT to GAT HIV-1 Specific RTI UC-10 (645129) Y ? 16 - - (35)
V 179 E GTT to GAG HIV-1 Specific RTI L-697,661 N Y 8 - - (23)
Y 181 C TAT to TGT HIV-1 Specific RTI Ï-APA R18893 (loviride- Y ? - - - (64)
-analogue)
Y 181 C TAT to TGT HIV-1 Specific RTI BHAP U-87201E (atevirdine) N Y - - K103N and Y181C observed with monotherapy (46)
Y 181 C TAT to TGT HIV-1 Specific RTI BHAP U-88204E Y ? - - - (34)
Y 181 C TAT to TGT HIV-1 Specific RTI BHAP U-90152 (delavirdine) ? Y - - K103N/Y181C seen separately and in (46)
combination in vivo
Y 181 C TAT to TGT HIV-1 Specific RTI BM+51.0836 Y ? - - - (65)
Y 181 C TAT to TGT HIV-1 Specific RTI DMP 266 (L-743,726) Y ? 4 - L100I/V179D/Y181C: 1,000-fold; uncommon (31, 32)
in vivo
Y 181 C TAT to TGT HIV-1 Specific RTI E-EBU Y ? - - - (52)
Y 181 C TAT to TGT HIV-1 Specific RTI E-EPSeU Y ? >50 - Y188C confers greater resistance than Y181C (66)
Y 181 C TAT to TGT HIV-1 Specific RTI E-EPU Y ? >95 - Y188C confers greater resistance than Y181C (66)
Y 181 C TAT to TGT HIV-1 Specific RTI MKC442 (1-EBU) ? Y - - - (51)
Y 181 C TAT to TGT HIV-1 Specific RTI L-697,593 Y ? >100 - K103N/Y181C: > 1,000-fold (47)
Y 181 C TAT to TGT HIV-1 Specific RTI L-697,661 Y Y >30 - K103N and Y181C most common
with monotherapy (24, 48)
Y 181 C TAT to TGT HIV-1 Specific RTI Loviride
(R89439, Ï-APA) ? Y - - - (67)
Y 181 C TAT to TGT HIV-1 Specific RTI Nevirapine Y Y >100 Other NNRTIs Can suppress
effects of AZT mutations (25, 68, 69)
Y 181 C TAT to TGT HIV-1 Specific RTI NSC 648400
(E-BPTU) Y ? 160 Other NNRTIs - (70)
Y 181 C TAT to TGT HIV-1 Specific RTI TIBO R82913 Y ? >100 - K103N/Y181C:> 1,000-fold (29)
Y 181 C TAT to TGT HIV-1 Specific RTI Trovirdine Y ? - Nevirapine;
n 9-chloro-
TIBO V179D/Y181C:> 1,000-fold;
Found in combination with K103R or V179D (44, 45)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-10
(645129) Y ? 6 - K101E/Y181C: 200-fold (36, 42)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-32
(645542) Y ? 3 - - (36)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-38
(629243) Y ? 8-149 Other NNRTIs - (36, 71)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-040 Y ? 16 - - (42)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-57
(647014) Y ? - - K101E/Y181C: 58-fold (36)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-68
(638532) Y ? 5 - - (36)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-69
(646989) Y ? - - V106A/V181C: 166-fold (36)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-80
(639475) Y ? 1 - - (36)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-81
(615727) Y ? 53 - - (35, 72)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-82 Y ? 5 - - (42)
Y 181 C TAT to TGT HIV-1 Specific RTI UC-84
(615985) Y ? >11 - - (36)
Y 181 C TAT to TGT HIV-1 Specific RTI UC781 Y ? 13 - V108/ Y181C: 55 fold; K101E/
V108I/ Y181C: 500 fold. (42)
Y 181 C TAT to TGT HIV-1 Specific RTI 1737
(Tetrahydronaphthalene
derivative) Y ? 20 - Y181C also confers resistance
to numerous other
tetrahydronaphthalene derivative (73)
Y 181 I TGT to ATT HIV-1 Specific RTI BHAP U-88204E Y Y - - Appeared after treatment of Y181C-
mutated virus with BHAP; high-level
resistance to BHAP, nevirapine and
TIBO; observed in one nevirapine-
treated patient (74)
Y 181 I TAT to ATT HIV-1 Specific RTI MKC442 (I-EBU) Y N 1,000 - - (60)
Y 181 I TGT to ATT HIV-1 Specific RTI Nevirapine N Y High-level - Observed in one patient (75)
M 184 I ATG to ATA Nucleoside RTI 3TC (lamivudine) Y Y - - M184V and M184I can suppress
effects of AZT resistance mutations (76, 77, 78)
M 184 T - Nucleoside RTI 3TC (lamivudine) Y ? - - Reduced replication capacity and RT
activity (79, 80)
M 184 V ATG to GTG Nucleoside RTI 3TC (lamivudine) Y Y >100 ddI; ddC;
(-)-FTC M184V and M184I can suppress effects
of AZT resistance mutations; GTA seen
in cell culture (76, 77, 78)
M 184 V ATG to GTG Nucleoside RTI (-)-FTC Y ? >100 - M184V can suppress effects of AZT
mutations (76, 77)
M 184 V ATG to GTG Nucleoside RTI 1592U89 Y N 3 - K65R/L74V and/or Y115F with M184V:
10-fold; K65R/M184V: 8-fold; L74V/
M184V: 9-fold resistance; L74V/Y115F
/M184V: 11-fold (8)
M 184 V ATG to GTG Nucleoside RTI ddC Y Y 2-5 - - (81)
M 184 V ATG to GTG Nucleoside RTI ddI Y Y 2-5 - Rarely observed in patients receiving ddI (81)
M 184 V ATG to GTG Nucleoside RTI L-FddC Y ? >100 - - (82)
Y 188 C TAT to TGT HIV-1 Specific RTI E-EPSeU Y ? >250 - Y188C is the predominant mutation for
E-EPSeU; Y188C confers greater resistance
than Y181C (66)
Y 188 C TAT to TGT HIV-1 Specific RTI E-EPU Y ? >250 - Y188C confers greater resistance
than Y181C (66)
Y 188 C TAT to TGT HIV-1 Specific RTI HEPT Y ? - - - (52)
Y 188 C TAT to TGT HIV-1 Specific RTI Nevirapine N Y - - - (30)
Y 188 H TAT to CAT HIV-1 Specific RTI BHAP U-87201E
(atevirdine) N Y - - K101E, Y188H, E233Y and K238T
observed with U-87201E/AZT
combination therapy (41)
Y 188 H TAT to CAT HIV-1 Specific RTI TIBO R82913 Y ? - - - (27)
Y 188 H/L TAT to CAT/CTT HIV-1 Specific RTI Loviride (R89439,
Ï-APA) ? Y - - - (67)
Y 188 L TAT to TTA HIV-1 Specific RTI DMP 266 (L-743,726) Y ? 1,000 - - (31)
Y 188 L TAT to TTA HIV-1 Specific RTI TIBO R82913 N Y - - - (63)
V 189 I GTA to ATA HIV-1 Specific RTI HBY 097 Y ? 2 Other NNRTIs
(2-6) - (16)
G 190 A GGA to GCA HIV-1 Specific RTI Loviride (R89439,
Ï-APA) ? Y - - - (83)
G 190 A GGA to GCA HIV-1 Specific RTI Nevirapine N Y - - - (25)
G 190 E GGA to GAA HIV-1 Specific RTI AAP-BHAP (U-104489) Y ? >100 - T139I/ G190E/ T200A/ L214F:
>100. Additional mutations possibly
restore the replication capacity of
the G190E mutant (84)
G 190 E GGA to GAA HIV-1 Specific RTI HBY 097 Y ? - Other NNRTIs Reduces enzymatic activity of RT
and viral replication competency (85)
G 190 E GGA to GAA HIV-1 Specific RTI S-2720 Y ? - - - (86)
G 190 E GGA to GAA HIV-1 Specific RTI UC-38 (629243) Y N - K101E/G190E: >100-fold; cross resistance
to: TSAO-m3T, Nev, TIBO R82913, BHAP
U88204; susceptible to L697,661 (35, 43)
G 190 E GGA to GAA HIV-1 Specific RTI AAP-BHAP (U-95133) Y ? >100 - T139I/ G190Q/ T200A/ L214F: >100-fold.
Additional mutations possibly restore
the replication compentency of the G190E
mutant. (84)
G 190 Q GGA to CAA HIV-1 Specific RTI HBY 097 Y ? - Other NNRTIs Appears exclusively in connection with V179D (16)
G 190 T GGA to ? HIV-1 Specific RTI HBY 097 - - - - Appears under lowered drug concentration
selection (54)
H 208 Y CAT to TAT Pyrophosphate
Analogue RTI Foscarnet (PFA) Y Y - 2 Q161L/H208Y: 9-fold; increased susceptibility
to AZT (100-fold), nevirapine (20-fold)
and TIBO R82150 (30-fold); Q161L/H208Y
suppresses effects of AZT mutations (20)
H 208 Y CAT to TAT Multiple Nucleoside
Resistance AZT + 3TC ? Y - - Polymorphism facilitating AZT+3TC dual
resistance (87)
L 210 W TTG to TGG Nucleoside RTI AZT Y Y - - 210W/215Y: 42-fold 41L/210W/215Y:
49-fold 41L/67N/70R/210W/215Y:
366-fold Mutation arises after prolonged
AZT therapy. (88, 89, 90)
R 211 K AGG to AAG Multiple
Nucleoside Resistance AZT + 3TC ? Y - - Polymorphism facilitating AZT+3TC dual
resistance in association with M184V and
other AZT resistance mutations. (87)
L 214 F CTT to TTT Multiple
Nucleoside Resistance AZT + 3TC ? Y - - Polymorphism facilitating AZT+3TC dual
resistance in association with M184V and
other AZT resistance mutations. (87, 91)
T 215 F ACC to TTC Nucleoside RTI AZT ? Y - - K67N/K70R/T215Y/K219Q: 120-fold (1, 2, 3)
T 215 Y ACC to TAC Nucleoside RTI AZT Y Y - - M41L/T215Y: 60-70-fold; K67N/K70R/
T215Y/K219Q: 120-fold. Effect of T215Y
is reversed by a ddI mutation (L74V),
NNRTI mutations (L100I;Y181C) or
(-)-FTC/3TC mutations (M184I/V) (1, 2, 3)
Y 215 C TTC to TGC Nucleoside RTI ddC N Y 4 - Arises on background of T215Y
AZT resistance (92)
K 219 E AAA to GAA Nucleoside RTI AZT Y N - - - (1, 2, 3)
K 219 Q AAA to CAA Nucleoside RTI AZT ? Y - - K67N/K70R/T215Y/K219Q: 120-fold (1, 2, 3)
P 225 H CCT to CAT HIV-1 Specific RTI S-2720 (Quinoxaline) Y ? - - P225H follows V106A. Also seen with
L101I and Y181C. Double and triple
mutants highly resistant to other
NNRTI's, including MKC442. (53)
E 233 V GAA to GTA HIV-1 Specific RTI BHAP U-87201E
(atevirdine) N Y - - K101E, Y188H, E233Y and K238T observed
with U-87201E/AZT combination therapy (41)
P 236 L CCT to CTT HIV-1 Specific RTI BHAP U-87201E
(atevirdine) Y N - - - (93)
P 236 L CCT to CTT HIV-1 Specific RTI BHAP U-90152
(delavirdine) Y Y - - Sensitizes RT ~10-fold to nevirapine,
TIBO R82913 and L-697,661 (93)
P 236 L CCT to CTT HIV-1 Specific RTI HEPT Y ? - - - (70)
K 238 T AAA to ACA HIV-1 Specific RTI BHAP U-87201E
(atevirdine) N Y - - K101E, Y188H, E233Y and K238T observed
with U-87201E/AZT combination therapy (41)
G 333 D GGC to GAC Multiple Nucleosides AZT+3TC Y Y - - Facilitates dual resistance to AZT+3TC
in association with M184V and standard
AZT resistance mutations. (87)
G 333 E GGC to GAG Multiple Nucleosides AZT + 3TC Y Y - - Facilitates dual resistance to AZT+3TC
in association with M184V and standard
AZT resistance mutations. (87)
Mutations in Protease and Drug Resistance
K 65 R AAA to AGA Nucleoside RTI ddC Y Y 4-10 - - (6, 7)
R 8 K CGA to AAA Protease Inhibitor A-77003 Y ? 10 - R8K/ M46I/ G48V: 20-fold (94, 95)
R 8 Q CGA to CAA Protease Inhibitor A-77003 Y ? 10 - M46I improves replication
competency of R8Q mutant (94, 96)
L 10 F CTC to TTC Protease Inhibitor DMP 450 Y ? - - Probably compensatory (97, 98)
L 10 F CTC to GGC Protease Inhibitor VB 11,328 Y ? - - L10F/I84V: 8-fold (99)
L 10 F CTC to CGC Protease Inhibitor VX-478 (141W94) Y ? - - - (100)
L 10 F CTC to CGC Protease Inhibitor XM323 - - - L10F/ V82A: 2-fold; L10F/ K45I/ I84V: 50-fold (101)
L 10 F CTC to CGC Protease Inhibitor SC-55389A Y ? 2.8 Not SC-52151 N88S/L10F: 25-fold (102, 103, 104)
L 10 F CTC to TTC Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 BS (360) L10F/ L23I/ V32I/ M46I/ I47V/
I54M/ A71V/ I84V: 1,500-fold.
Associated Gag mutations: p1/p6
cleavage site (L to F (CTT to
TTT at P1'); p7/p1 cleavage site
(Q to R (CAG to CGG) at P3',
A to V (GCT to CTT) at P2'. (106)
L 10 I CTC to ATC Protease Inhibitor MK-639 (L-735
,524, indinavir) ? Y - - (105)
L 10 I - Protease Inhibitor Ro 31-8959
(saquinavir) - Y - - Found in combination with
G48V in vivo (107)
L 10 R CTC to CGC Protease Inhibitor MK-639 (L-735,524,
indinavir) - N Y XM-323 (15) L10R/ M46I/ L63P/ V82T:
4-fold; L10R/ M46I/ L63P/
V82T/ I84V: 8-fold (105)
L 10 V CTC to GTC Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - A-80987 (4) - (105)
K 20 M AAG to ATG Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - VX-478 (8) - (105)
K 20 R AAG to AAA Protease Inhibitor ABT-538 (ritonavir) N Y - - K20R/M36I/I54V/V82A: 41-fold (108)
K 20 R AAG to AAA Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - Ro-31-8959 (8); - (105)
L 23 I CTA to ATA Protease Inhibitor BILA 2185 BS Y ? - Ro 31-8959 (50);L-735,
524 (80); BILA 1906
BS (360) L10F/ L23I/ V32I/ M46I/ I47V/
I54M/ A71V/ I84V: 1,500-fold.
Associated Gag mutations: p1/p6
cleavage site (L to F (CTT to
TTT at P1'); p7/p1 cleavage site
(Q to R (CAG to CGG) at P3',
A to V (GCT to CTT) at P2'. (106, 109)
L 24 I TTA to ATA Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - SC-52151 (8) - (105)
L 24 V TTA to GTA Protease Inhibitor SC-52151 Y ? 10-20 SC55389A L24V/ G48V/ A71V/
V75I/ P81T: 1000-fold (102, 103)
D 30 N GAT to AAT Protease Inhibitor AG1343
(nelfinavir) Y Y - - D30N/A71V: 7-fold; D30N
and N88D are most common
in vivo after 24 weeks of
therapy; they do not cause
cross-resistance to other
protease inhibitors (110, 111)
V 32 I GTA to ATA Protease Inhibitor ABT-538 (ritonavir) Y ? 40 - V32I and V82I are synergistic
mutations yielding 20-fold
enzyme resistance (108)
V 32 I GTA to ATA Protease Inhibitor A-77003 Y ? 7
(enzyme resist.) - V32I appears first; progression
to V32I/ M46V and V32I/ /
M46V/ A71V/ V82A occurs even
in the absence of drug (96)
V 32 I GTA to ATA Protease Inhibitor BILA 1906 BS Y ? - - V32I/ A71V: 3-fold; V32I/
M46I,L/ A71V/ I84V: 5-fold;
V32I/ M46I,L/ A71V/ I84A:
520-fold. 32I/ 46L/ 71V/
84A are functionally impaired.
Associated Gag mutations:
p1/p6 cleavage
site (L to F
(CTT to TTT at P1') (112, 106)
V 32 I GTA to ATA Protease Inhibitor BILA 2011
(palinavir) Y ? 1200 BILA 1906 (1400) Other mutations found in
p1/ p6 cleavage site (113)
V 32 I GTA to ATA Protease Inhibitor KNI-272 Y ? 2 - V32I/ M46I/ I84V: 37-fold;
V32I/ L33F/ K45I/ F53L/
A71V/ I84V/ L89M: 130-fold (114)
V 32 I GTA to ATA Protease Inhibitor MK-639 (L-735,
524, indinavir) Y Y - - V32I/ M46L/ V82A: 3-fold;
V32I/ M46L/ A71V/ V82A:
14-fold (105)
V 32 I GTA to ATA Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 (360) L10F/ L23I/ V32I/ M46I/ I47V/
I54M/ A71V/ I84V: 1,500-fold.
Associated Gag mutations:
p1/p6 cleavage site (L to F
(CTT to TTT at P1'); p7/ p1
cleavage site (Q to R
(CAG to CGG) at P3', A to V
(GCT to CTT) at P2'. (106)
L 33 F TTA to TTC Protease Inhibitor ABT-538 (ritonavir) N Y - - M36I/I54V/A71V/V82I: 8-fold;
K20R/M36I/I54V/V82A: 41-fold.
In vivo, V82A/F/T/S occurs first,
often followed by changes at
54,71 and 36 (108)
M 36 I ATG to ATA Protease Inhibitor ABT-538 (ritonavir) N Y - - In vivo, V82 occurs first,
often followed by changes at
54, 71 and 36 (108)
M 36 I - Protease Inhibitor AG1343 (nelfinavir) - Y - - - (110)
K 45 I AAA to ATA Protease Inhibitor XM323 - - - - L10F/ K45I/ I84V:
50-fold (95)
M 46 F ATG to TTC Protease Inhibitor A-77003 Y ? 4
(enzyme resist.) - Seen with V82A (96)
M 46 I ATG to ATA Protease Inhibitor A-77003 Y ? - - No effect on susceptibility
but improves replication
competency of R8Q mutant;
R8K/ M46I/ G48V: 20-fold (94, 96)
M 46 I ATG to ATA Protease Inhibitor ABT-538 (ritonavir) Y Y - - M46I/ L63P/ A71V/ V82F/
I84V: 27-fold (108)
M 46 I ATG to ATA Protease Inhibitor AG1343 (nelfinavir) Y Y - - - (110)
M 46 I ATG to ATA Protease Inhibitor BILA 1906 BS Y ? - - L 735,524 (60)&V32I/ A71V:
3-fold; V32I/ M46I,L/ A71V/
I84V: 5-fold; V32I/ M46I,L/
A71V/ I84A: 520-fold. V32I/
M46L/A71V/I84A is functionally
impaired. Associated Gag
mutations: p1/p6 cleavage site
(L to F (CTT to TTT at P1') (106, 109, 112, 113)
M 46 I ATG to ATA Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 (360) L10F/ L23I/ V32I/ M46I/ I47V/
I54M/ A71V/ I84V: 1,500-fold.
Associated Gag mutations:
p1/p6 cleavage site (L to F
(CTT to TTT at P1'); p7/p1
cleavage site (Q to R
(CAG to CGG) at P3', A to V
(GCT to CTT) at P2'. (106)
M 46 I ATG to ATA Protease Inhibitor DMP 450 Y ? - - Probably compensatory (97, 98)
M 46 I ATG to ATA Protease Inhibitor MK-639 (L-735,524,
indinavir) N Y - - M46I/ L63P/ V82T: 4-fold;
L10R/ M46I/ L63P/ V82T:
4-fold; L10R/ M46I/ L63P/
V82T/ I84V: 8-fold (105, 115)
M 46 I ATG to ATA Protease Inhibitor VB 11,32 Y ? - - I50V/ M46I/ I47V:
20-fold (95, 99)
M 46 I ATG to ATA Protease Inhibitor VX-478 (141W94) Y ? Nil - - -
M 46 L ATG to TTC Protease Inhibitor A-77003 Y ? 2-3
(enzyme resist.) - - (96)
M 46 L ATG to TTG Protease Inhibitor BILA 1906 BS Y ? - - Associated p1/ p6 cleavage
site mutation (L to F
(CTT to TTT) at P1' (106, 109, 112, 113)
M 46 L ATG to TTG Protease Inhibitor MK-639 (L-735,524,
indinavir) Y Y - - V32I/ M46L/ A71V/ V82A:
14-fold; V32I/ M46L/
V82A: 3-fold&(95)\cr
M 46 L ATG to CTG Protease Inhibitor XM323 Y ? - - V82A/ M46L: 7-fold; V82A/
M46L/ L97V: 11-fold (101)
M 46 V - Protease Inhibitor A-77003 Y ? - - V32I appears first; progression
to V32I/ M46V and V32I/ /
M46V/ A71V/ V82A occurs even
in the absence of drug (95)
I 47 V ATA to CTA Protease Inhibitor VB 11,328 Y ? - - I50V/ M46I/ I47V: 20-fold -
I 47 V ATA to CTA Protease Inhibitor VX-478 (141W94) Y ? Nil - - -
I 47 V ATA to CTA Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 (360) L10F/ L23I/ V32I/ M46I/ I47V/
I54M/ A71V/ I84V: 1,500-fold.
Associated Gag mutations:
p1/p6 cleavage site (L to F
(CTT to TTT at P1'); p7/p1
cleavage site (Q to R (CAG
to CGG) at P3', A to V
(GCT to CTT) at P2'. (106)
G 48 V GGG to GTG Protease Inhibitor A-77003 Y ? - - R8K/ M46I/ G48V: 20-fold;
G48V/ I82T: 100-fold (116)
G 48 V GGG to GTG Protease Inhibitor Ro 31-8959
(saquinavir) Y Y - - Found in comb. with L10I in
vivo; G48V/ I84V/ L90M:
30-fold; G48V/ L90M: >100-fold
enzyme resistance; G48V/ L90M/
I54V: > 50-fold
(subtype B or O) (117, 118)
G 48 V GGG to GTG Protease Inhibitor SC-52151 Y ? - - Ro 31-8959&G48V/ V82A, G48V/
L63P/ V82A or I54T: 10- to
20-fold; L24V/ G48V/ A71V/
V75I/ P81T: 1000-fold (102, 103)
G 48 V GGG to GTG Protease Inhibitor MP-167 Y ? 20 MP-134(5) SC-52151
(16) Ro31-8959(5)
(Fold increase in
IC90s). L10F/G48V:20-fold (119)
G 48 V GGG to GTG Protease Inhibitor MK-639 (L-735,524,
Indinavir) ? Y - - - (120)
I 50 V ATT to GTT Protease Inhibitor VB 11,328 Y ? 3 - I50V/ M46I/ I47V:
20-fold (95)
I 50 V ATT to GTT Protease Inhibitor VX-478 (141W94) Y ? 3 - - (121)
I 54 M ATT to ATG Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 (360) L10F/ L23I/ V32I/ M46I
/ I47V/ I54M/ A71V/ I84V:
1,500-fold. Associated
Gag mutations: p1/p6
cleavage site (L to F
(CTT to TTT at P1');
p7/p1 cleavage site
(Q to R (CAG to CGG) at
P3'; A to V (GCT to CTT)
at P2'. (106)
I&54 V ATC to GTC Protease Inhibitor ABT-538 (ritonavir) N Y - - I54V/V82T: 9-fold;
K20R/M36I/I54V/V82A:
41-fold; M36I/I54V/A71V/
V82T: 8-fold; I54V/A71V/
V82A/L90N: 7-fold; In vivo,
V82A/F/T/S occurs first,
followed by changes at
54, 71 and 36 (108)
I 54 V ATC to GTC Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - - - (112)
I 54 V ATA to GTA Protease Inhibitor Ro 31-8959
(saquinavir) Y - - - In subtype O -
I 54 V ATC to GTC Protease Inhibitor Ro 31-8959
(saquinavir) Y - - - In subtype B (117, 118)
D 60 E GAT to GAA Protease Inhibitor DMP 450 Y ? - - Probably compensatory (97, 98)
L 63 P CTC to CCC Protease Inhibitor MK-639 (L-735,524,
indinavir) N Y - - M46I/ L63P/ V82T:
4-fold; L10R/ M46I/
L63P/ V82T/ I84V:
8-fold; L10R/ M46I/
L63P/ V82T: 4-fold (105)
A 71 T GCT to ACT Protease Inhibitor BMS 186,318 Y ? - - A71T/ V82A: 15-fold (122, 123)
A 71 T GCT to ACT Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - - - (105)
A 71 V - Protease Inhibitor A-77003 Y ? - - V32I appears first;
progression to V32I/
M46V and V32I/ / M46V/
A71V/ V82A occurs even
in the absence of drug;
M46I/ L63P/ A71V/ V82F/
I84V: 27-fold (95, 101)
A 71 V GCT to GTT Protease Inhibitor ABT-538 (ritonavir) Y Y - - - (108)
A 71 V GCT to GTT Protease Inhibitor AG1343 (nelfinavir) Y ? 5 - D30N/ A71V: 7-fold;
M46I/ L63P/ A71V/
I84V: 30-fold -
A 71 V GCT to GTT Protease Inhibitor BILA 1906 BS Y ? - - V32I/ A71V: 3-fold; V32I/
M46I,L/ A71V/ I84V: 5-fold;
V32I/ M46I,L/ A71V/ I84A:
520-fold. 32I/ 46L/ 71V/
84A are functionally impaired.
Associated Gag mutations:
p1/p6 cleavage site (L to F
(CTT to TTT at P1') (106, 109, 112, 113)
A 71 V GCT to GTT Protease Inhibitor BILA 2011 (palinavir) Y ? - BILA 2185: 30-fold - (112)
A 71 V GCT to GTT Protease Inhibitor MK-639 (L-735,524,
indinavir) Y Y - - V32I/ M46L/ A71V/ V82A:
14-fold (95)
A 71 V GCT to GTT Protease Inhibitor SC-52151 Y ? - Not L-735,524 A71V/ V75I/ P81T: 20- to
m 30-fold; L24V/ G48V/ A71V/
V75I/ P81T: 1000-fold; N88D
or I11V/ M46I/ F53L/ A71V/
N88D:10- to 20-fold (102, 103)
A 71 V GCT to GTT Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 (360) L10F/ L23I/ V32I/ M46I/ I47V/
I54M/ A71V/ I84V: 1,500-fold.
Associated Gag mutations:
p1/p6 cleavage site (L to F
(CTT to TTT at P1'); p7/p1
cleavage site (Q to R
(CAG to CGG) at P3'; A to V
(GCT to CTT) at P2'. (106)
G 73 S GGT to GCT Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - Emerges following a switch
from saquinavir to indinavir. (124)
V 75 I GTA to ATA Protease Inhibitor SC-52151 Y ? - - L24V/ G48V/ A71V/ V75I/
P81T: 1000-fold; A71V/ V75I/
P81T: 20- to 30-fold; L24V/
G48V/ A71V/ V75I/ P81T:
1000-fold (102, 103)
V 77 I - Protease Inhibitor AG1343 (nelfinavir) Y Y - - - -
P 81 T CCT to ACT Protease Inhibitor SC-52151 Y ? - - A71V/ V75I/ P81T: 20- to
30-fold; L24V/ G48V/ A71V/
V75I/ P81T: 1000-fold (102, 103)
I 82 T ATC to ACC Protease Inhibitor A-77003 Y ? - - G48V/ I82T: 100-fold
(82T was derived from in
vitro passage of 82I) (125)
V 82 A GTC to GCC Protease Inhibitor A-77003 Y ? - - Rare; seen with M46F;
V32I appears first;
progression to V32I/ M46V
and V32I/ / M46V/ A71V/
V82A occurs even in the
absence of drug (95, 116, 125)
V 82 A GTC to GCC Protease Inhibitor ABT-538 (ritonavir) N Y 2 - In vivo, V82 occurs first,
often followed by changes
at I54, A71 and M36 (108)
V 82 A GTC to GCC Protease Inhibitor BMS 186,318 Y ? - A-77003 (4) A71T/ V82A: 15-fold (122, 123)
V 82 A GTC to GCC Protease Inhibitor MK-639 (L-735,524,
indinavir) Y Y - - V32I/ M46L/ V82A: 3-fold;
V32I/ M46L/ A71V/ V82A:
14-fold (105)
V 82 A GTC to GCC Protease Inhibitor P9941 Y ? 6-8 - - (126)
V 82 A GTC to GCC Protease Inhibitor SC-52151 Y ? - - G48V/ V82A, G48V/ L63P/
V82A or I54T: 10- to
20-fold -
V 82 A - Protease Inhibitor SKF108922 Y ? - - -
V 82 A GTC to GCC Protease Inhibitor XM323 Y ? - - V82A/ M46L: 7-fold; V82A/
M46L/ L97V: 11-fold; L10F/
V82A: 2-fold; ; V82A/
L97V: 3-fold (101)
V 82 A GTC to GCC Protease Inhibitor Ro 31-8959
(saquinavir) ? Y - - Follows G48V during
saquinavir therapy or
after a switch to nelfinavir
or indinavir. (127, 128, 129)
V 82 F GTC to TTC Protease Inhibitor ABT-538 (ritonavir) Y Y - - V82F/ I84V: 8- to 10-fold;
M46I/ L63P/ A71V/ V82F/
I84V: 27-fold (108)
V 82 F GTC to TTC Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - - - (99)
V 82 F GTC to TTC Protease Inhibitor XM323 Y ? - - V82F/ I84V: 92-fold (101)
V 82 I GTC to ATC Protease Inhibitor A-77003 Y ? - - No resistance alone but
V32I and V82I are synergistic
mutations yielding 20-fold
enzyme resistance (82T was
derived from in vitro passage
of 82I) (96)
V 82 I GTC to ATC Protease Inhibitor XM323 Y ? <2 - - (101)
V 82 S GTC to TCC Protease Inhibitor ABT-538 (ritonavir) N Y 6 - In vivo, V82 occurs first,
often followed by changes
at I54, A71 and M36 (108)
V 82 T GTC to ACC Protease Inhibitor ABT-538 (ritonavir) N Y 3 - In vivo, V82 occurs first,
often followed by changes
at I54, A71 and M36; V82T
has reduced replication
efficacy in natural
background (108)
V 82 T GTC to ACC Protease Inhibitor MK-639 (L-735,524,
indinavir) N Y - - M46I/ L63P/ V82T: 4-fold;
L10R/ M46I/ L63P/ V82T:
4-fold; L10R/ M46I/ L63P/
V82T/ I84V: 8-fold (105)
V 82 T - Protease Inhibitor SKF108842 Y ? - - - (130)
V 82 T - Protease Inhibitor SKF108922 Y ? - - - -
I 84 A ATA to GCA Protease Inhibitor BILA 1906 BS Y ? - BILA 2185 BS (200) V32I/ A71V: 3-fold; V32I/
M46I,L/ A71V/ I84V: 5-fold;
V32I/ M46I,L/ A71V/ I84A:
520-fold. 32I/ 46L/ 71V/
84A are functionally
m impaired. Associated Gag
mutations: p1/p6 cleavage
site (L to F (CTT to TTT
at P1') (106, 109, 112, 113)
I 84 A ATG to ATA Protease Inhibitor BILA 2011 (palinavir) Y ? - Ro 31-8959 (400); I84A is the most
common mutation (112)
I 84 V ATA to GTA Protease Inhibitor ABT-538 (ritonavir) Y Y - - M46I/ L63P/ A71V/
V82F/ I84V: 27-fold;
V82F/ I84V: 8- to
10-fold; M46I/ L63P/
A71V/ V82F/ I84V:
27-fold (108)
I 84 V ATA to GTA Protease Inhibitor AG1343 (nelfinavir) - ? - - M46I/ L63P/ A71V/
I84V: 30-fold (110)
I 84 V ATA to GTA Protease Inhibitor BILA 1906 BS Y ? - BILA 2185 BS(200) V32I/ A71V: 3-fold;
V32I/ M46I,L / A71V/
I84V: 5-fold; V32I/ M46I,
L/ A71V/ I84A: 520-fold.
32I/ 46L/ 71V/ 84A are
functionally impaired.
Associated Gag mutations:
p1/p6 cleavage site (L
to F (CTT to TTT at P1') (106, 109, 112, 113)
I 84 V ATA to GTA Protease Inhibitor BILA 2185 BS Y ? - BILA 1906 BS(360) L10F/ L23I/ V32I/ M46I/
I47V/ I54M/ A71V/ I84V:
1,500-fold. Associated
Gag mutations: p1/p6
cleavage site (L to F
(CTT to TTT at P1');
p7/p1 cleavage site
(Q to R (CAG to CGG) at
P3', A to V (GCT to CTT)
at P2'. (106)
I 84 V ATA to GTA Protease Inhibitor DMP 450 Y ? - - - (97, 98)
I 84 V ATA to CTA Protease Inhibitor MK-639 (L-735,524,
indinavir) N Y - - G48V/ I84V/ L90M: 30-fold;
L10R/ M46I/ L63P/ V82T/
I84V: 8-fold (105)
I 84 V ATA to GTA Protease Inhibitor Ro 31-8959
(saquinavir) Y ? - - - (95)
I 84 V ATA to GTA Protease Inhibitor RPI-312 Y ? 5 - - (131)
I 84 V - Protease Inhibitor SKF108842 Y ? - - - -
I 84 V ATA to GTA Protease Inhibitor VB 11,328 Y ? - - L10F/ I84V: 8-fold -
I 84 V ATA to GTA Protease Inhibitor VX-478 (141W94) Y ? - - - -
I 84 V ATA to GTA Protease Inhibitor XM323 Y ? 12 P9941; not A-77003
or Ro 31-8959 V82F/ I84V: 92-fold;L10F/
K45I/ I84V:50-fold (95, 101)
I 84 V ATA to GTA Protease Inhibitor MP-134 Y ? 10 MP-167(5) ABT-
538(10) MK-639(8)
SC-52151(8) Ro31-895(2)
(IC90 data) - (132)
N 88 D - Protease Inhibitor AG1343 (nelfinavir) Y Y - - D30N and N88D are most
common in vivo after 24
weeks of therapy; they
do not cause cross-
resistance to other
protease inhibitors (110)
N 88 D AAT to GAT Protease Inhibitor SC-52151 Y ? - - N88D compensatory,
no resistance alone (132)
N 88 S AAT to AGT Protease Inhibitor SC-55389A Y ? 20 L735,524 (3);
not SC-52151 N88S/L10F: 25 (104)
L 90 M TTG to ATG Protease Inhibitor ABT-538 (ritonavir) N Y - - 82A/ 54V/ I/ 71V/
90L/ M: 7-fold (108)
L 90 M TTG to ATG Protease Inhibitor AG1343 (nelfinavir) N Y - - Rare in patients (110)
L 90 M TTG to ATG Protease Inhibitor MK-639 (L-735,524,
indinavir) ? Y - - - (105)
L 90 M TTG to ATG Protease Inhibitor Ro 31-8959
(saquinavir) Y Y - - G48V/ L90M: >100-fold
enzyme resistance; double
mutant rare in vivo; L90M
most common in vivo;
G48V/ I84V/ L90M:
30-fold (117)
L 97 V TTA to GTA Protease Inhibitor XM323 Y ? - - No resistance alone;
V82A/L97V: 3-fold;
V82A/ M46L/ L97V:
11-fold (101)
Mutations in Envelope and Drug Resistance
Amino Acid Codon Class of Drug Compound In In -Fold Cross-resistace comments Refs
Change channge vitro Vivo -resistance (-fold)
R 22 A AGG to AGA Fusion/ Binding Inhibitor RPR103611 Y ? - - - (132)
I 84 S ATC to AGC Fusion/ Binding Inhibitor RPR103611 Y ? - - - (132)
S 113 N AGT to AAT Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - S113N/ S134N/ K269E/
Q278E/ N293D/
N323S/ R387I: 250-fold;
113 is in the V1 loop region (132, 133)
S 134 N AGC to AAC Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - V2 loop region; S113N/
S134N/ K269E/
Q278E/ N293D/ N323S/
R387I: 250-fold (133, 134)
F 145 L TTC to TTA Fusion/ Binding Inhibitor JM-3100 Y ? - - Combination of mutations:
2- to 100-fold (135, 136)
N 188 K AAT to AAA Fusion/ Binding Inhibitor Siamycin I Y ? - - N188K/ G332E/ N351D/
A550T/ N633D/ L762S:
9-fold (137)
I 228 V ATA to GTA Fusion/ Binding Inhibitor JM-2763 Y ? - - Combination of mutations -
K 269 E AAA to GAA Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - V3 loop region; S113N/
S134N/ K269E/
Q278E/ N293D/ N323S/
R387I: 250-fold (133, 134)
N 270 S AAT to AGT Fusion/ Binding Inhibitor JM-3100 Y ? - - - -
R 272 T AGA to ACA Fusion/ Binding Inhibitor JM-3100 Y ? - - - -
S 274 R AGT to AGA Fusion/ Binding Inhibitor JM-2763 Y ? - - Combination of mutations:
95- to 792-fold (135, 136)
S 274 R AGT to AGA Fusion/ Binding Inhibitor JM-3100 Y ? DS (> 7 to 6,667) -
Q 278 H CAG to CAT Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - V3 loop region; S113N/
S134N/ K269E/
Q 278E/ N293D/ N323S/
R387I: 250-fold (133, 134)
Q 278 H CAG to CAT Fusion/ Binding Inhibitor JM-2763 Y ? - - -
Q 278 H CAG to CAC Fusion/ Binding Inhibitor JM-3100 Y ? - - -
I 288 V ATA to GTA Fusion/ Binding Inhibitor JM-3100 Y ? - - -
N 293 D AAT to GAT Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - V3 loop region; S113N/
S134N/ K269E/ Q278E/
N293D/ N323S/ R387I:
250-fold (133, 134)
N 293 H AAT to CAT Fusion/ Binding Inhibitor JM-3100 Y ? - - -
A 297 T GCA to ACA Fusion/ Binding Inhibitor JM-2763 Y ? - - - -
A 297 T GCA to ACA Fusion/ Binding Inhibitor JM-3100 Y ? - - - -
N 323 S AAT to AGT Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - C3 region; S113N/
S134N/ K269E/ Q278E/
N293D/ N323S/ R387I:
250-fold (133, 134)
G 332 E GGA to GAA Fusion/ Binding Inhibitor Siamycin I Y ? - - N188K/ G332E/ N351D/
A550T/ N633D/ L762S:
9-fold (137)
N 351 D AAT to GAT Fusion/ Binding Inhibitor Siamycin I Y ? - - N188K/ G332E/ N351D/
A550T/ N633D/ L762S:
9-fold (137)
P 385 L CCA to CTA Fusion/ Binding Inhibitor JM-2763 Y ? - - -
P 385 L CCA to CTA Fusion/ Binding Inhibitor JM-3100 Y ? - - -
R 387 I AGA to ACA Fusion/ Binding Inhibitor Dextran sulphate
(DS) Y ? - - CD4 binding region;
S113N/ S134N/ K269E/
Q278E/ N293D/ N323S/
R387I: 250-fold (133, 134)
Q 410 E CAA to GAA Fusion/ Binding Inhibitor JM-3100 Y ? - - -
S 433 P TCC to CCC Fusion/ Binding Inhibitor JM-3100 Y ? - - -
V 457 I GTA to ATA Fusion/ Binding Inhibitor JM-3100 Y ? - - -
A 550 T GCC to ACC Fusion/ Binding Inhibitor Siamycin I Y ? - - N188K/ G332E/ N351D/
A550T/ N633D/ L762S:
9-fold (137)
N 633 D AAT to GAT Fusion/ Binding Inhibitor Siamycin I Y ? - - N188K/ G332E/ N351D/
A550T/ N633D/ L762S:
9-fold (137)
L 762 S TTG to TCG Fusion/ Binding Inhibitor Siamycin I Y ? - - N188K/ G332E/ N351D/
A550T/ N633D/ L762S:
9-fold (137)
Mutations in SIV Reverse Transccriptase and Drug Resistance
Amino Acid Codon Class of Drug Compound In In -Fold Cross-resistace comments Refs
Change channge vitro Vivo -resistance (-fold)
K 65 R AAA to AGA SIV Nucleoside RT Inhibitor PMPA ? Y 5 3TC (80); ddI; ddC; d4T; K65R appears first, followed by (138, 139, 140)
PMEA N69S and I118V. Observed changes
at N69S and I118V do not result
in increased resistance.
Q 151 M CAG to ATG SIV Nucleoside RT Inhibitor AZT ? Y >100 ddI; ddC; d4T; 3TC - (141)
M 184 V ATG to GTG SIV Nucleoside RT Inhibitor (-)-FTC Y ? - - - (82)
Mutations in FIV Reverse Transcriptase and Drug Resistance
Amino Acid Codon Class of Drug Compound In In -Fold Cross-resistace comments Refs
Change channge vitro Vivo -resistance (-fold)
L 74 I TTA to ATA HIV-1 Specific RTI HBY 097 Y ? - - - (16)
D 3 H GAT to CAT FIV Nucleoside RT Inhibitor ddC Y ? 4 ddI; PFA - (142, 143)
V 47 I GTA to ATA FIV Nucleoside RT Inhibitor d4T Y ? 4-6 PFA (>50); AZT; ddI; PMEA - (144)
P 156 S CCA to TCA FIV Nucleoside RT Inhibitor 3TC Y ? 7 AZT (4), AZT + 3TC (6) - (145)
M 183 T ATG to ACG FIV Nucleoside RT Inhibitor (-)-FTC Y ? 10 ddC Corresponds to 184 in HIV; M183V (146)
recombinant displays 10-fold
resistance to 3TC or (-)-FTC.
Abbreviations
Amino acids
A alanine
C cysteine
D aspartate
E glutamate
F phenyalanine
G glycine
H histidine
I isoleucine
K lysine
L leucine
M methionine
N asparagine
P proline
Q glutamine
R arginine
S serine
T threonine
V valine
W tryptophan
Y tyrosine
Compounds
1592U89 (1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate (a carbovir analogue, Glaxo Wellcome)
3TC (-)-§-L-2',3'-dideoxy-3'-thiacytidine (Glaxo Wellcome)
1737 Tetrahydronapthalene lignan derivative
Ï-APA R18893 Ï-nitro-anilino-phenylacetamide
A-77003, A-75925 C2 symmetry-based protease inhibitors (Abbott Laboratories)
and A-80987
AAP-BHAP bisheteroarylpiperazine analogue (Pharmacia & Upjohn)
ABT-538 C2 symmetry-based protease inhibitor (Abbott Laboratories)
AZdU 3'-azido-2',3'-dideoxyuridine
AZT 3'-azido-3'-deoxythymidine (Glaxo Wellcome)
AZT-p-ddI 3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxyinosinic acid (Ivax)
BHAP bisheteroarylpiperazine
BILA 1906 N-1S-[[[3-[2S-(1,1-dimethylethyl)amino]carbonyl-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide (Bio-Mega/Boehringer Ingelheim)
BILA 2185 N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethyphenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidine-carboxamide (Bio-Mega/Boehringer Ingelheim)
BM+51.0836 thiazolo-isoindolinone derivative
BMS 186,318 aminodiol derivative HIV-1 protease inhibitor (Bristol-Myers Squibb)
d4API 9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanel]adenine (Gilead Sciences)
d4C 2',3'-didehydro-2',3'-dideoxycytidine
d4T 2',3'-didehydro-3'-deoxythymidine (Bristol-Myers Squibb)
ddC 2',3'-dideoxycytidine (Roche)
ddI 2',3'-dideoxyinosine (Bristol-Myers Squibb)
DMP 266 a 1,4-dihydro-2H-3,1-benzoxazin-2-one
DMP 450 [4R-(4-Ï,5-Ï,6-§,7-§)]-hexahydro-5,6-bis(hydroxy)-1,3-bis(3-amino)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one-bismesylate (Avid Therapeutics)
DXG (-)-§-D-dioxolane-guanosine
EBU-dM 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil
E-EBU 5-ethyl-1-ethoxymethyl-6-benzyluracil
DS dextran sulphate
E-EPSeU 1-(ethoxymethyl)-(6-phenylselenyl)-5-ethyluracil
E-EPU 1-(ethoxymethyl)-(6-phenyl-thio)-5-ethyluracil
F-ddA 2'-fluoro-2',3'-dideoxyadenosine
(-)-FTC (-)-§-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (Triangle Pharmaceuticals)
HBY 097 (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione
HEPT 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine
JM2763 1,1'-(1,3-propanediyl)-bis-1,4,8,11-tetraazacyclo-tetradecane (Johnson Matthey)
JM3100 1,1'-[1,4-phenylenebis-(methylene)]bis-(1,4,8,11-tetra\-azacyclo\-tetra\-decane) octa\-hydro\-chloride dihydrate (Johnson Matthey)
KNI-272 (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containing tripeptide
L-697,593 5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-one
L-697,661 3-[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino-5-ethyl-6-methylpyridin-2(1H)-one
L-FDDC (-)-§-L-5-fluoro-2',3'-dideoxy-cytidine
L-FDOC (-)-§-L-5-fluoro-dioxolane cytosine
MK-639 hydroxy-aminopentane amide HIV-1 protease inhibitor (Merck \ Co)
MKC442 6-benzyl-1-ethoxymethyl-5-isopropyluracil (I-EBU, Triangle Pharmaceuticals/Mitsubishi)
MP-134 C2 symmetry-based protease inhibitor
MP-167 C2 symmetry-based protease inhibitor
nevirapine 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol[3,2-b:2',3'-e] diazepin-6-one (Boehringer Ingelheim)
NNRTI non-nucleoside reverse transcriptase inhibitor
NSC648400 1-benzyloxymethyl-5-ethyl-6-(Ï-pyridylthio)uracil (E-BPTU)
P9941 [2-pyridylacetyl-IIePheAla-y(CHOH)]\sub2 (Dupont Merck)
PFA phosphonoformate (foscarnet, Astra)
PMEA 9-(2 phosphonylmethoxyethyl)adenine (Gilead Sciences)
PMPA (R)-9-(2-phosphonyl-methoxypropyl)adenine (Gilead Sciences)
Ro 31-8959 hydroxyethylamine derivative HIV-1 protease inhibitor (Roche)
RPI-312 1-[(3S)-3-(n-Ï-benzyloxycarbonyl)-l-asparginyl)-amino-2-hydroxy-4-phenyl-butyryl]-n-tert-butyl-l-proline amide (peptidyl protease inhibitor)
RPR103611
RT reverse transcriptase
S-2720 6-chloro-3,3-dimethyl-4-(isopropenyl-oxycarbonyl)-3,4-dihydro-quinoxalin-2(1H)thione
SC-52151 hydroxyethylurea isostere protease inhibitor (Searle)
SC-55389A hydroxyethyl-urea isostere protease inhibitor (Searle)
TIBO R82150 (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (Janssen)
TIBO 82913 (+)-(5S)-4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)-imidazo-[4,5,1-jk]-[1,4]benzo-diazepin-2(1it\ H)-thione (Janssen)
TSAO-m$^3$T [2',5'-bis-O-(tert-butyl-dimethylsilyl)-3'-spiro-5'-(4'-amino-1',2'-oxathiole-2',2'-dioxide)]-§-D-pentofuranosyl-N$^3$-methylthymine
U-90152 1-[3-[(1-methylethyl)-amino]-2-pyridinyl]-4-[[5-[(methylsulphonyl)-amino]-lH-indol-2yl]carbonyl]-piperazine
U-95133 (Alkylamino)piperidine bis(heteroaryl)piperizine analog
U-104489 (Alkylamino)piperidine bis(heteroaryl)piperizine analog
UC-040 thiocarboxanilide derivative (Uniroyal Chemical Co)
UC thiocarboxanilide derivatives (Uniroyal Chemical Co)
UC-781 N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furan-carbothioamide
UC-82 N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophene-carbothioamide
VB 11,328 hydroxyethyl-sulphonamide protease inhibitor (Vertex Pharmaceuticals)
VX-478 hydroxyethylsulphonamide protease inhibitor (Vertex Pharmaceuticals)
XM 323 cyclic urea protease inhibitor (Dupont Merck)
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140. Van Rompay K, Cherrington J, Marthas M, Agatep E, Dehqanzada Z, Lamy P, Berardi C, Bischofberger N, Pedersen N. Therapeutic efficacy of PMPA treatment for infant macaques infected with PMPA-resistant simian immunodeficiency virus. 6th International Workshop on HIV Drug Resistance, 25-28 June 1997; St. Petersburgh, USA: Abstract 117.
141. Van Rompey KKA, Breenier JL, Marthas ML, Otsyula MG, Tarar RP, Miller CJ, Pedersen NC. A zidovudine resistant simian immunodefiency virus mutant with a Q151M mutation in reverse transcriptase causes AIDS in newborn macaques. Antimicrob Agents Chemother 1997; 41:278-283.
142. Medlin HK, Zhu Y, Remington KM, Phillips TR, North TW. Selection and characterization of a mutant of feline immunodeficiency virus resistant to 2',3'-dideoxycytidine. Antimicrob Agents Chemother 1996; 40:953-957.
143. Zhu Y-Q, Remington KM, North TW. Mutants of feline immunodeficiency resistance to 2',3'-dideoxy-2',3'-didehydrothymidine. Antimicrob Agents Chemother 1996; 40:1983-1987.
144. Smith RA, Reminton KM, Lloyd RM Jr., Schinazi RF, North TW. A novel point mutation at position 156 of reverse transcriptase from feline immunodeficiency virus confers resistance to the combination of (-)-§-L-2',3'-dideoxy-3'-thiacytidine and 3'-azido-3'-deoxythymidine. J Virol 1997; submitted for publication.
145. Smith R, Remington K, Lloyd R, Schinazi R, North T. Mutants of feline immunodeficiency virus resistant to FTC and 3TC. Third International Feline Retrovirus Research Symposium, 1996, Ft. Collins, CO: Abstract 41.
146. Smith RA, Remington K, Lloyd RM Jr, Schinazi RF, North TW. A novel met to thr mutation in the YMDD motif of reverse transcriptase from feline immunodeficiency virus confers resistance to oxathiolane nucleosides. J Virol 1997; 71:2357-2362.