Major Protease Inhibitor (PI) Resistance Mutations
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.
L10I/V are polymorphic accessory PI-selected mutations that either reduce PI susceptibility or increase the replication of viruses containing PI-resistance mutations (6,7). L10R/Y are rare nonpolymorphic PI-selected mutations (8,4,9). Their effects on PI susceptibility have not been well studied.
V11I is a minimally polymorphic accessory mutation that is often selected in patients receiving DRV (10,11). It is associated with minimal reductions in DRV and FPV susceptibility (4). It is included in the Tibotec DRV genotypic susceptibility score (12). V11L is a less common nonpolymorphic PI-selected mutation that is also associated with reduced susceptibility to DRV and FPV (1,4,5).
K20I is the consensus amino acid in subtype G and CRF02_AG viruses. However, in most other subtypes, it is a PI-selected mutation associated with reduced NFV susceptibility (15,4). K20M/V are uncommon relatively nonpolymorphic PI-selected mutations that have not been well studied (8). K20R is a highly polymorphic PI-selected accessory mutation that increases replication fitness in viruses with PI-resistance mutations (16).
L24I is a nonpolymorphic mutation selected by IDV and, less often, LPV (18,19,13,20). It is associated with reduced susceptibility to FPV, IDV, LPV, SQV, ATV and NFV (1,15,21). It increases susceptibility to TPV (1,22).
L24F is an uncommon nonpolymorphic PI-selected accessory mutation that appears to have a susceptibility profile similar to L24I (8,1). L24M is a rare nonpolymorphic PI-selected mutation that has not been well studied (4).
V32I is a nonpolymorphic substrate-cleft mutation selected by IDV, FPV, LPV and DRV (23,30,18,31,32,10,11,33,34,35). It reduces susceptibility to each of the PIs except SQV (1,21,15,4). It is included in the Tibotec DRV genotypic susceptibility score (12). V32I usually occurs in combination with I47 mutations (36). In combination with I47V it causes intermediate resistance to both LPV and DRV and lays the groundwork for higher levels of resistance with additional DRMs. In combination with I47A it causes high-level LPV resistance and intermediate DRV resistance.
L33F occurs in up to 1.0% of subtype A, CRF01_AE, and CRF02_AG viruses from ARV-naive patients but is otherwise nonpolymorphic. It is selected by each of the PIs except ATV, IDV and SQV (23,37,38,13,32,10,11,12,39,35,40). When it occurs in combination with other PI-resistance mutations it is associated with reduced susceptibility to each of the PIs (1,41,15). It is included in the Tibotec DRV genotypic susceptibility score (12).
L33I is a minimally polymorphic PI-selected mutation (23) that does not appear to reduce PI susceptibility. L33V is a polymorphic mutation that is not selected by any of the PIs and does not reduce PI susceptibility (1,4).
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 (23). In subtype B viruses, M36I increases the replication fitness of viruses with PI-resistance mutations (16,42).
K43T is a nonpolymorphic PI-selected accessory mutation (23,14,13). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV genotypic susceptibility score (41,43). In combination with other PI-resistance mutations, it is associated with reduced susceptibility to TPV and possibly other PIs (1,41,4,44).
M46I/L are nonpolymorphic mutations selected primarily by IDV, NFV, FPV, ATV and LPV (18,30,13,37,23,20,25,45,40). In ARV-naive patients, M46I/L occur in about 0.1% to 0.4% of viruses, with the highest prevalence occurring in CRF01_AE. M46I and L occur in about 20% and 10% of PI-treated patients, respectively. M46I usually occurs alone or in combination with V32I, I47V, L76V, I84V, and L90M. M46L usually occurs alone or in combination with I54V and V82A (36). M46I increases PR catalytic efficiency (46,47). M46I/L are associated with reduced susceptibility to ATV, FPV, IDV, LPV and NFV (1,15,48,21,47). M46L also reduces susceptibility to TPV and is part of the Boehringer-Ingelheim TPV genotypic susceptibility score (41,43). M46V is a rare nonpolymorphic PI-selected mutation that has not been well studied.
I47V is a nonpolymorphic mutation selected by IDV, FPV, LPV and DRV (31,34,37,38,19,13,10,11,33). It is associated with reduced susceptibility to each of the PIs except SQV and ATV (1,44,15). I47V is included in the Tibotec DRV genotypic susceptibility score (12).
I47A is a 2-base-pair nonpolymorphic mutation selected by LPV (19,49). It confers high-level resistance to LPV and FPV and low/intermediate-level resistance to the remaining PIs except ATV and SQV (50,48,15,51,1). It increases susceptibility to SQV (1,15,51). It usually occurs in combination with V32I, with which it acts synergistically to reduce susceptibility to IDV, LPV and DRV (52,51).
G48V is a nonpolymorphic substrate-cleft mutation selected by SQV and, less often, by IDV and LPV (23,53,54,55). It confers high-level resistance to SQV, intermediate resistance to ATV and low-level resistance to NFV, IDV and LPV (1,4,56).
G48A/S/T/Q/L are extremely rare nonpolymorphic PI-selected mutations (8) that occur primarily in viruses containing multiple PI-resistance mutations. These mutations appear to have similar but weaker effects on PI susceptibility than G48V and G48M (4).
I50V is a nonpolymorphic substrate-cleft mutation selected by FPV, LPV and DRV (37,13,57,10,11,4). It reduces susceptibility to these PIs (1,15,44,58,2) and increases susceptibility to TPV (22). It is included in the Tibotec DRV genotypic susceptibility score (12).
F53L is a nonpolymorphic mutation selected primarily by SQV, IDV, ATV and LPV (23,37,13,40) and reduces susceptibility to these PIs as well as NFV (1,15). F53Y is an uncommon nonpolymorphic PI-selected mutation that has not been well studied (8,4).
I54M is a nonpolymorphic mutation selected primarily by FPV, LPV and DRV (23,66,34,10). It reduces susceptibility to these PIs and causes cross-resistance to the remaining PIs (1,2,44,15). It is included in the Tibotec DRV genotypic susceptibility score (12).
I54L is a nonpolymorphic mutation selected primarily by FPV, LPV and DRV (23,66,34,10). It reduces susceptibility to these PIs and causes cross-resistance to the remaining PIs except IDV and TPV (1,2,44,15). It increases susceptibility to TPV (43). It is included in the Tibotec DRV genotypic susceptibility score (12).
I54A/T/S are nonpolymorphic PI-selected mutations that occur almost exclusively in viruses with multiple PI-resistance mutations. I54A/T/S are associated with reduced susceptibility to each of the PIs except DRV (1,15,41,65,4).
Q58E is a nonpolymorphic PI-selected accessory mutation selected by most PIs (23). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV genotypic susceptibility score (41,43). It is likely associated with low-level resistance to several other PIs (1,15,4).
A71V/T are common polymorphic PI-selected accessory mutations (23) that increase replication and/or reduce PI susceptibility in viruses containing PI-resistance mutations (16,67,15,4). A71I/L are nonpolymorphic accessory PI-selected mutations that generally occur in viruses containing multiple PI-resistance mutations (8).
G73S/T/C/A are non-polymorphic accessory mutations selected primarily by SQV, ATV, IDV and NFV (8,13,37,59,54,18). G73S/T/C/A are associated with reduced susceptibility to each of the PIs (1,15,4,2). G73V/D are rare nonpolymorphic PI-selected mutation that has not been well studied (8).
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 (1,22,41,4). It is included in the Boehringer-Ingelheim TPV and Tibotec DRV genotypic susceptibility scores (41,43,12).
T74S is a PI-selected accessory mutation that is polymorphic in most non-B subtypes (68).
L76V is selected by IDV, LPV and DRV (30,69,70,11,71,72). It reduces susceptibility to these PIs and to FPV (1,15,2). It increases susceptibility to ATV, SQV and TPV (1,15,73,72). L76V is included in the Tibotec DRV genotypic susceptibility score (12).
V82A is a nonpolymorphic substrate-cleft mutation selected primarily by IDV and LPV (23,18,74,75,30,20). V82A reduces susceptibility to these PIs and is associated with cross-resistance to ATV and NFV (1,15,21,18). 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 mutations selected by ATV, IDV, LPV and TPV (23,18,74,75,20,40). They reduce susceptibility to these PIs and to NFV and ATV (1,15,44,41). V82T is included in the Boehringer-Ingelheim TPV genotypic susceptibility score (43,39).
V82F is a nonpolymorphic substrate-cleft mutation selected primarily in patients who have received IDV or multiple PIs (76,37,23,18,35). It reduces susceptibility to IDV as well as to DRV, FPV, LPV, and NFV (1,15,2,18).
V82L is an uncommon nonpolymorphic substrate-cleft mutation selected primarily by TPV (41). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV genotypic susceptibility score (41,43). It reduces TPV susceptibility but its effects on other PIs are not well characterized (1,4).
V82M is an uncommon nonpolymorphic PI-selected mutation. In most subtypes, it requires a 2-bp mutation and occurs in viruses from patients with multiple PI-resistance mutations (41,8). In subtype G, it usually requires a single bp mutation and has been reported it patients who have received IDV (77). It reduces susceptibility to IDV and possibly LPV and other PIs (77,4).
V82C is an uncommon nonpolymorphic 2-base-pair PI-selected substrate-cleft mutation that occurs in viruses with multiple PI-resistance mutations (8,41). Its effect on PI susceptibility has not been well studied.
N83D is a nonpolymorphic PI-selected accessory mutation (8) associated with reduced susceptibility to ATV, SQV, NFV, IDV and TPV (1,4,41,22,43,4). It was first recognized as a PI-resistance mutation because of its inclusion in the Boehringer-Ingelheim TPV genotypic susceptibility score (41,43). N83S is an extremely rare nonpolymorphic PI-selected mutation that has not been well studied.
I84V is a nonpolymorphic substrate-cleft mutation selected by each of the PIs (23), including IDV (18,31), LPV (37,76), DRV (32,11), SQV (78,79) and TPV (39). I84V reduces susceptibility to each of the PIs (21,41,15,1,2).
I84A/C are extremely rare non-polymorphic PI-selected mutations (80). I84A is associated with high level resistance to each of the PIs (15,80). I84C has a less-marked effect on PI susceptibility (15,80).
N88S is a nonpolymorphic mutation selected by NFV, ATV, and occasionally IDV (29,81,25,26,82,23). It reduces susceptibility to these PIs (1,15,48) and increases susceptibility to FPV (83,1,15,84). It confers low-level cross-resistance to SQV (1,15,48).
N88D is a nonpolymorphic mutation selected by NFV, usually in combination with D30N (29,25,85,82,27,28,86,52). N88D appears to compensate for the reduced replication fitness associated with D30N and appears to be associated with low-level cross-resistance to ATV and SQV (1,15,86).
N88G/T are extremely rare nonpolymorphic PI-selected mutations (8) weakly associated with reduced NFV and ATV susceptibility.
L89V is a nonpolymorphic accessory mutation selected by IDV, NFV, FPV, LPV and DRV (23,32,10,11). It reduces susceptibility to these PIs. L89V is included in the Tibotec DRV genotypic susceptibility score (12). L89T is an extremely rare non-polymorphic PI-selected mutation of uncertain phenotypic and clinical significance (8).
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