Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

PI Resistance Notes

Last updated March 2, 2014

Major Protease Inhibitor (PI) Resistance Mutations
 
  30 32 33 46 47 48 50 54 76 82 84 88 90
Cons D V L M I G I I L V I N L
ATV/r   I F IL V VM L VTALM   ATFS V S M
DRV/r   I F   VA   V LM V F V    
FPV/r   I F IL VA   V VTALM V ATSF V   M
IDV/r   I   IL V     VTALM V AFTS V S M
LPV/r   I F IL VA VM V VTALM V AFTS V   M
NFV N   F IL V VM   VTALM   AFTS V DS M
SQV/r           VM   VTALM   AT V S M
TPV/r   I F IL VA     VAM   TL V    
The table lists the most common clinically significant PI-resistance mutations. Those in bold red are associated with the highest levels of phenotypic resistance and/or with the strongest clinical evidence for interfering with successful PI therapy. Those mutations that are underlined are potential contraindications to the use of the relevant PI.

L10F/I/V/R/Y
L10F is a common nonpolymorphic accessory PI-selected mutation. It reduces in vitro susceptibility to each of the PIs except ATV, SQV, and TPV (1,2,3,4).

L10I/V are polymorphic accessory PI-selected mutations that either reduce PI susceptibility or increase the replication of viruses containing PI-resistance mutations (5,6).

L10R/Y are rare nonpolymorphic accessory PI-selected mutations (7,4). Their effects on PI susceptibility have not been well studied.

V11I/L
V11I is a minimally polymorphic accessory mutation that is often selected in patients receiving DRV (8,9). It is associated with minimal reductions in DRV and FPV susceptibility (4). It is included in the Tibotec DRV GSS (10). V11L is a less common nonpolymorphic mutation that is also associated with minimal reductions in in vitro susceptibility to DRV and FPV (1,4).

K20R/I/M/T/V
K20T is a nonpolymorphic accessory PI-selected mutation (11,12,7) that is associated with reduced susceptibility to each of the PIs except SQV and TPV (1,2).

K20I is the consensus amino acid in subtype G and CRF02_AG. In subtypes B and C, K20I is a PI-selected mutation that appears to reduce NFV susceptibility (13,4).

K20M/V are uncommon relatively nonpolymorphic PI-selected mutations that have not been well studied (7).

K20R is a highly polymorphic accessory PI-selected mutation that increases replication fitness in viruses with PI-resistance mutations (14).

L23I
L23I is an uncommon nonpolymorphic substrate cleft mutation that is selected primarily by NFV (15). It causes low/intermediate-level resistance to NFV (15).

L24I/F/M
L24I is a nonpolymorphic mutation selected by IDV and, less often, LPV (16,17,11,18). It reduces susceptibility to FPV, IDV, LPV, SQV, ATV and NFV (1,13,19). It increases susceptibility to TPV (1,20).

L24F is an uncommon nonpolymorphic accessory PI-selected mutation that appears to have a susceptibility profile similar to L24I (7,1). L24M is a rare nonpolymorphic PI-selected mutation that has not been well studied (4).

D30N
D30N is a nonpolymorphic NFV-selected substrate-cleft mutation (21,22,23,24,25,26) that causes high-level resistance to NFV (1,13,27).

V32I
V32I is a nonpolymorphic substrate-cleft mutation selected by IDV, FPV, LPV and DRV (21,28,16,29,30,8,9,31,32,33). It reduces susceptibility to each of the PIs except SQV (1,19,13,4). It is included in the Tibotec DRV GSS (10).

L33F/I/V
L33F occurs in up to 1.0% of ARV-naive patients in subtype A, CRF01_AE, and CRF02_AG but is otherwise nonpolymorphic. It is selected by each of the PIs except ATV, IDV and SQV (21,34,35,11,30,8,9,10,36,33,37). When it occurs in combination with other PI-resistance mutations it is associated with reduced susceptibility to DRV, FPV, LPV, TPV and possibly NFV (1,38,13). It is included in the Tibotec DRV GSS (10).

L33I is a minimally polymorphic PI-selected mutation (21) that does not appear to reduce PI susceptibility.

L33V is a polymorphic mutation that is not selected by any of the PIs (21). It does not reduce PI susceptibility (4).

E35G
E35G is a relatively nonpolymorphic PI-selected mutation. It is weakly associated with reduced NFV and TPV susceptibility (1,38,4).

M36I
M36I is the consensus amino acid in most of the non-B subtypes. It occurs in about 15% of PI-naive and 35% of PI-experienced individuals with subtype B viruses (21). In subtype B viruses, M36I increases the replication fitness of viruses with PI-resistance mutations (14,39).

K43T
K43T is a nonpolymorphic PI-selected accessory mutation (21,12,11). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV genotypic susceptibility score (38,40). In combination with other PI-resistance mutations, it is associated with reduced susceptibility to TPV and most other PIs (1,38,4,41).

M46I/L/V
M46I/L are nonpolymorphic mutations selected primarily by IDV, NFV, FPV, ATV and LPV (16,28,11,34,21,18,23,42,37). M46I usually occurs in combination with V32I, I47V, L76V, I84V, and L90M. M46L usually occurs in combination with I54V and V82A (43). M46I increases PR catalytic efficiency (44,45). M46I/L reduce susceptibility to ATV, FPV, IDV, LPV and NFV (1,13,46,19,45). M46L also reduces susceptibility to TPV and is part of the Boehringer-Ingelheim tipranavir genotypic susceptibility score (38,40). M46V is a rare nonpolymorphic PI-selected mutation that has not been well studied.

I47V/A
I47V is a nonpolymorphic mutation selected by IDV, FPV, LPV and DRV (29,32,34,35,17,11,8,9,31). It is associated with reduced susceptibility to each of the PIs except SQV and ATV (1,41,13). I47V is included in the Tibotec DRV GSS (10).

I47A is a 2-base-pair nonpolymorphic mutation selected by LPV (17,47). It confers high-level resistance to LPV and FPV and low/intermediate-level resistance to the remaining PIs except ATV and SQV (48,46,13,49,1). It increases susceptibility to SQV (1,13,49). It usually occurs in combination with V32I, with which it acts synergistically to reduce susceptibility to IDV, LPV and DRV (50,49).

G48V/M/A/S/T/Q
G48V is a nonpolymorphic substrate-cleft mutation selected by SQV and, less often, by IDV and LPV (21,51,52,53). It confers high-level resistance to SQV , intermediate-level resistance to ATV and low-level resistance to NFV, IDV and LPV (1,4,54).

G48M is a 2-base-pair nonpolymorphic substrate-cleft mutation selected in patients who have received multiple PIs. It causes high-level resistance to SQV, intermediate-level resistance to ATV and NFV and low-level resistance to IDV and LPV (1,41,50,13).

G48A/S/T/Q/L are extremely rare nonpolymorphic PI-selected mutations (7) that occur primarily in viruses containing multiple PI-resistance mutations. These mutations appear to have similar but weaker effects on PI susceptibility than do G48V and G48M (4).

I50V/L
I50V is a nonpolymorphic substrate-cleft mutation selected by FPV, LPV and DRV (34,11,55,8,9,4). It reduces susceptibility to these PIs (1,13,41,56,2) and increases susceptibility to TPV (20). It is included in the Tibotec DRV GSS (10).

I50L is a nonpolymorphic mutation selected by ATV (21,57,58,59,60). I50L confers high-level resistance to ATV and increases susceptibility to the remaining PIs (1,57,58,59,61).

F53L/Y
F53L is a nonpolymorphic mutation selected primarily by SQV, IDV, ATV and LPV (21,34,11,37) and reduces susceptibility to these PIs as well as NFV (1,13). F53Y is an uncommon nonpolymorphic PI-selected mutation that has not been well studied (7,4).

I54V/A/S/T/L/M
I54V is a nonpolymorphic mutation selected primarily by IDV (21,16,62,53) and LPV (21,34,11,35,17). It reduces susceptibility to each of the PIs except DRV (1,13,63,19).

I54M is a nonpolymorphic mutation selected primarily by FPV, LPV and DRV (21,64,32,8). It reduces susceptibility to these PIs and causes cross-resistance to NFV, IDV, SQV, ATV and TPV (1,2,41,13). It is included in the Tibotec DRV GSS (10).

I54L is a nonpolymorphic mutation selected primarily by FPV, LPV and DRV (21,64,32,8). It reduces susceptibility to these PIs and causes cross-resistance to NFV, SQV, and ATV and possibly IDV (1,2,41,13). It increases susceptibility to TPV (40). It is included in the Tibotec DRV GSS (10).

I54A/T/S are nonpolymorphic PI-selected mutations that occur almost exclusively in patients who have received multiple PIs. I54A/T/S reduce susceptibility to each of the PIs except DRV (1,13,38,63,4).


Q58E
Q58E is a nonpolymorphic accessory mutation selected by most PIs (21). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV genotypic susceptibility score (38,40). It is associated with low-level resistance to most PIs (1,13,4).


A71V/T/I/L
A71V/T are common polymorphic PI-selected accessory mutations (21) that increase replication and/or reduce PI susceptibility in viruses containing PI-resistance mutations (14,65,13,4). A71I/L are nonpolymorphic accessory PI-selected mutations that generally occur in viruses from patients receiving multiple PIs (7).

G73S/T/C/A/V
G73S/T/C/A are non-polymorphic accessory mutations selected primarily by SQV, ATV, IDV and NFV (7,11,34,57,52,16). G73S/T/C/A reduce susceptibility to each of the PIs except possibly TPV (1,13,4,2). G73V is a rare nonpolymorphic PI-selected mutation that has not been well studied (7).

T74P/S
T74P is a nonpolymorphic PI-selected accessory mutation that occurs primarily in viruses from patients who have received multiple PIs. It is associated with reduced susceptibility to each of the PIs (1,20,38,4). It is included in the Boehringer-Ingelheim TPV and Tibotec DRV GSS (38,40,10).

T74S is an PI-selected accessory mutation that is nonpolymorphic in subtype B viruses but polymorphic in non-B viruses. It occurs in up to 10% of subtype C viruses from untreated patients (21). In subtype B viruses it is selected by NFV (66) and SQV (21).


L76V
L76V is selected by IDV, LPV and DRV (28,67,68,9,69,70). It reduces susceptibility to these PIs and to FPV (1,13,2). It increases susceptibility to ATV, SQV and TPV (1,13,71,70). L76V is included in the Tibotec DRV GSS (10).


V82AT/S/F/L/M/C
V82A is a nonpolymorphic substrate-cleft mutation selected primarily by IDV and LPV (21,16,72,73,28,18). V82A decreases susceptibility to these PIs and confers cross-resistance to ATV and NFV (1,13,19,16). It is also associated with reduced susceptibility to SQV and FPV when it occurs in combination with additional PI-resistance mutations.

V82T/S are nonpolymorphic substrate-cleft mutations selected by ATV, IDV, LPV and TPV (21,16,72,73,18,37). They reduce susceptibility to these PIs and to NFV and ATV (1,13,41,38). V82T is included in the Boehringer-Ingelheim TPV genotypic susceptibility score (40,36).

V82F is a nonpolymorphic substrate-cleft mutation selected primarily in patients who have received IDV ofr multiple PIs (74,34,21,16,33). It reduces susceptibility to IDV as well as to DRV, FPV, LPV, and NFV (1,13,2,16).

V82L is an uncommon nonpolymorphic substrate-cleft mutation primarily selected by TPV (38). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV GSS (38,40). It reduces TPV susceptibility but its effects on other PIs are not well characterized (1,4).

V82M is an uncommon nonpolymorphic PI-selected substrate-cleft mutation. In most subtypes, it requires a 2-bp mutation (GTC/T => ATG) and it occurs in viruses from patients who have received multiple PIs (38,7). In subtype G, it usually requires a single bp mutation (ATC/T => ATG) and has been reported it patients who have received IDV (75). It reduces susceptibility to IDV and LPV and possibly other PIs (75,4).

V82C is an uncommon nonpolymorphic 2-base-pair PI-selected substrate-cleft mutation that occurs in viruses from patients who have received multiple PIs (7,38). It appears to have an effect on susceptibility similar to V82A (4).

V82I is the consensus amino acid for position 82 in 90% of subtype G viruses and in 1% to 5% of the remaining subtypes (73,1).

N83D/S
N83D is a nonpolymorphic PI-selected accessory mutation (7) associated with reduced susceptibility to ATV, SQV, NFV, IDV and TPV (1,4,38,20,40,4). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV GSS (38,40). N83S is an extremely rare nonpolymorphic PI-selected mutation that has not been well studied.


I84V/A/C
I84V is a nonpolymorphic substrate-cleft mutation selected by each of the PIs (21), most frequently IDV (16,29), LPV (34,74), DRV (30,9), SQV (76,77) and TPV (36). I84V reduces susceptibility to each of the PIs (19,38,13,1,2).

I84A/C are extremely rare non-polymorphic PI-selected mutations (78). I84A is associated with the highest levels of phenotypic resistance observed for most of the PIs (13,78). I84C has a less-marked effect on PI susceptibility (13,78).


I85V
I85V is a nonpolymorphic PI-selected mutation (7). It has minimal, if any, effects on PI susceptibility (1).


N88D/S/T/G
N88D is a nonpolymorphic mutation selected by NFV, nearly always in combination with D30N (27,23,79,80,25,26,81,50). Together, N88D and D30N synergistically reduce susceptibility to NFV. N88D appears to compensate for the reduced replication fitness associated with D30N and may be associated with reduced susceptibility to ATV and SQV (1,13,81).

N88S is a nonpolymorphic mutation selected by NFV and ATV (27,82,23,24,80,21). It reduces susceptibility to these PIs (1,13,46) and increases susceptibility to FPV (83,1,13,84). It confers low-level cross-resistance to IDV and SQV (1,13,46).

N88G/T are extremely rare nonpolymorphic PI-selected mutations (7) weakly associated with reduced NVP and ATV susceptibility.


L89V
L89V is a nonpolymorphic accessory mutation selected by IDV, NFV, FPV, LPV and DRV (21,30,8,9). It reduces susceptibility to these PIs. L89V is included in the Tibotec DRV GSS (10). L89T is an extremely rare non-polymorphic PI-selected mutation (7) of uncertain phenotypic and clinical significance.

L90M
L90M is selected primarily by SQV, NFV, IDV and LPV (51,52,85,27,23,24,82,86,16,87,29,21,28). It reduces susceptibility to each of the PIs except TPV and DRV (1)

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