Major Nucleoside RT Inhibitor (NRTI) Resistance Mutations
The table lists the most common clinically significant NRTI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the relevant NRTI. Mutations in bold reduce NRTI susceptibility or virological response. Mutations in plain text contribute to reduced susceptibility in combination with other NRTI-resistance mutations.
M184V/I are selected by 3TC/FTC and reduce susceptibility to these drugs >100-fold. They are also selected by and cause low-level resistance to ABC and ddI (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15). In contrast, M184V/I increase susceptibility to AZT, d4T and TDF (16,17,18,19,3,20,4,5,13,21) and slows the emergence of AZT, d4T, and TDF resistance (22,23,24,17,25,26,27,28,29,30). M184V/I are associated with reduced viral replication in vitro and in vivo (31,32,33,34,35,36,37). M184I usually emerges before M184V because it results from a more common HIV-1 nucleotide substitution (38). However, M184V outcompetes M184I within several weeks of viral replication and is found in most patients with virological failure on 3TC or FTC (39,31).
K65R is selected by TDF, ABC, d4T, ddI, and rarely 3TC (40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59). It reduces TDF, ABC and ddI susceptibility ~2-fold and d4T susceptibility ~1.5-fold in the PhenoSense assay (60) –reductions that are well above the highest reductions observed in viruses from ARV-naïve patients (61,4,62,14,6,63). K65R + M184V/I appear sufficient to abrogate the NRTI activity of a regimen comprising ABC, TDF, or d4T plus a cytosine analog suggesting that despite the relatively low-levels of reduced susceptibility associated with K65R, this mutation is highly clinically relevant. K65R reduces 3TC and FTC susceptibility about 5 to 10-fold (3,64). This is considered low-level / intermediate resistance for these NRTIs because they have a much wider dynamic susceptibility range (the most resistant viruses have >200-fold reduced susceptibility to 3TC and FTC) and because K65R alone is usually not sufficient to abrogate the activity of 3TC and FTC in vivo. K65R is also selected by TAF and has a similar effect on TAF susceptibility as it does on TDF susceptibility (65).
K65R increases AZT susceptibility, except when it occurs in combination with Q151M (4,62,66,67,22,5,6,68,69,70,4). K65R rarely occurs in combination with TAMs because K65R and most TAMs exhibit bidirectional antagonism (68,71,72,73).
Several lines of evidence suggest that K65R is more likely to emerge in subtype C viruses than viruses belonging to other subtypes. First, biochemical studies have shown that the unique subtype C sequence context in the region of K65R, specifically – a span of five consecutive adenosines preceding the adenosine at the second position in the K65 codon – renders it more likely to be mutated during reverse transcription (74,75,72). Second, K65R has been reported to emerge more rapidly during in vitro passage of subtype C than subtype B viruses in the presence of TDF (76). Third, two retrospective studies have suggested that patients who develop VF on a TDF-containing regimen are at a somewhat higher risk of developing K65R if they are infected with a subtype C virus (77,78). Nonetheless, regardless of subtype, K65R is the most common NRTI-associated resistance mutation other than M184V to develop in patients receiving a TDF-containing regimen. There has also been no evidence that patients with subtype C viruses are at higher risk of developing VF on a TDF-containing regimen.
K65N is an uncommon NRTI-selected mutation that reduces susceptibility to TDF, 3TC/FTC, ABC and ddI (79,80,81,82). It has been reported primarily in patients receiving d4T or TDF plus 3TC/FTC (54,83,84,85). It also appears to increase susceptibility to AZT (80). K65E is an extremely rare, highly unfit NRTI-selected mutation (86) that usually occurs as part of an electrophoretic mixture with the wildtype K (63).
TAMs are non-polymorphic mutations selected by the thymidine analogs AZT and d4T. They reduce NRTI susceptibility by facilitating primer unblocking (aka nucleotide excision, pyrophosphorolysis) (87,88,89,90,91,92,93). The classical TAMs — M41L, D67N, K70R, L210W, T215Y/F and K219Q/E — were first reported in patients receiving AZT monotherapy (94,95,96,97). Several additional mutations are selected by AZT and d4T and/or facilitate primer unblocking, including T215 revertant mutations, additional amino acid variants at the classical TAM positions, and accessory mutations at other positions that contribute to reduced NRTI susceptibility.
The TAMs occur in two distinct but overlapping patterns: Type 1, which includes M41L, L210W, and T215Y; and Type 2, which includes D67N, K70R, T215F, and K219Q/E (30,98,99,100,101). Type 1 TAMs have a greater negative impact on virological response to an ABC-, ddI-, or TDF-containing regimen than do Type 2 TAMs (8,11,7,102,30,103,104). The near-uniform development of M184V during most virological failures blunts the effects of the TAMs on AZT, d4T, and TDF susceptibility but is associated with further reductions in susceptibility to ABC and ddI.
(i) M41L usually occurs in combination with T215Y. Together, M41L and T215Y confer high-level resistance to AZT and d4T and low-to-intermediate-level resistance to ABC, ddI and TDF. (ii) D67N reduces susceptibility primarily to AZT and d4T. When present with other TAMs it is also associated with reduced susceptibility to ABC, ddI and TDF. (iii) K70R confers intermediate-level resistance to AZT and low-level resistance to d4T and TDF. (iv) L210W usually occurs in combination with M41L and T215Y. Together, M41L, L210W and T215Y confer high-level resistance to AZT and d4T and intermediate to high-level resistance to ABC, ddI and TDF. (v) T215Y/F confer intermediate-level resistance to AZT and d4T and low-level resistance to ABC, ddI and TDF. (vi) K219Q/E reduce susceptibility to AZT and d4T when present with other TAMs.
Patients primarily infected with strains containing T215Y/F often develop viruses with the following reversion mutations (105,106,107): T215C/D/S, from the mutation of TAT/C (Y) to TGT/C (C), GAT/C (D), or TCT/C (S); T215I/V, from the mutation of TTT/A (F) to ATT/A (I) or GTT/A (V); and T215E from an additional revertant mutation GAT/C (D) to GAA/G (D) (107,108,109). Some ARV–naive patients with T215 revertants may be at increased risk of developing virological failure on AZT- or d4T-containing first line regimens because in contrast to the wild type threonine (T), most revertants require just a single base-pair change to develop T215Y/F and because the presence of a revertant by standard sequencing may indicate the presence of T215Y/F as a minority variant (110,111,112,113).
D67G/E and K219N/R are also selected by AZT and d4T and appear to contribute to reduced NRTI susceptibility in combination with other TAMs (114,115,4). In contrast to K70R, K70E/G/Q/T/N/S are NRTI-selected mutations that appear to increase susceptibility to AZT and reduce susceptibility to the remaining NRTIs (40,116,117,118).
E40F, E44D/A and V118I contribute to reduced NRTI susceptibility primarily in combination with other TAMs (119,120,121,122,123,4). V118I is polymorphic and occurs in 2% to 3% of ARV-naive patients; E40F and E44D/A are nonpolymorphic. K43Q/N, E203K, H208Y, D218E, K223Q/E and L228H/R are poorly characterized nonpolymorphic NRTI-selected mutations that usually occur in combination with multiple other TAMs (124,125,115,126,127).
K70E/G/Q/T/N/S are an uncommon nonpolymorphic mutations selected in patients receiving d4T, TDF and ABC-containing regimens (128,129,130,131,49,48,132,133,134,116,78,117,135,136). K70E/G and possibly K70Q/T/N/S reduce susceptibility to these NRTIs and cause potentially low-level resistance to 3TC/FTC. K70E/G and possibly K70Q/T/N/S increase AZT susceptibility (40,116,118).
L74V occurs commonly in patients receiving ABC or ddI; it also occurs occasionally in patients receiving TDF (137,83,138,78). The combination of L74V + M184V is the most common pattern of mutations to develop in patients receiving ABC/3TC (42,139,57,50,6). This combination reduces ABC susceptibility by >5-fold and ddI susceptibility >2-fold. L74V increases susceptibility to AZT and AZT treatment selects against the development of this mutation (139,140,141,4,13,142). In contrast, TDF treatment does not select against L74V even though this mutation increases susceptibility to TDF in vitro (143,141). L74V and L74I may have compensatory effects on viral fitness, particularly in the presence of NNRTI-resistance mutations, possibly explaining their occurrence even in patients receiving TDF (144,145).
L74I is selected primarily by ddI and ABC, and occasionally by TDF (146,147,114,83). It is appears less effective than L74V in reducing susceptibility to ABC and ddI in vitro. It does not appear to significantly increase AZT and TDF susceptibility (114).
Y115F is selected by ABC and TDF (42,80,148,80,1,149,51,3,47,48,49,83,138). Alone, Y115F reduces ABC susceptibility ~3-fold but has little phenotypic effect on TDF susceptibility. In combination with K65R or Q151M, Y115F synergistically reduces ABC and TDF susceptibility (14,80,4).
Q151M usually occurs in combination with two or more of the following four accessory mutations: A62V, V75I, F77L, and F116Y (142,150,151,152). Q151M alone causes high-level resistance to AZT, d4T, ddI and ABC, and low-level resistance to 3TC, FTC and TDF. In combination with two or more accessory mutations it causes intermediate-level resistance to 3TC, FTC and TDF (4,65). Q151L is an extremely rare highly unfit nonpolymorphic NRTI-selected mutation. Although it does not appear to reduce NRTI susceptibility, it represents a transition between wildtype and Q151M (153).
Beta3-Beta4 insertions occurring anywhere between codons 66 and 70 are by convention assigned to position 69. These insertions usually comprise a T69S substitution followed by two additional amino acids (154,155,156,157). T69 insertions usually occur in combination with multiple TAMs, and in this context they cause intermediate-level resistance to 3TC and FTC and high-level resistance to the remaining NRTIs. T69 insertions are the mutations associated with the greatest reductions in TDF susceptibility (4,158,65).
The most common Beta3-Beta4 deletions occur at positions 67, 69, and 70. Position 67 deletions usually occur in combination with the unusual mutation T69G and either Q151M or multiple TAMs (159,160,161). Viruses with position D67 deletions usually have high-level reductions in susceptibility to most NRTIs. T69 deletions usually occur in combination with K65R and/or Q151M (54). Viruses with T69 deletions plus K65R alone contribute reduced susceptibility to all NRTIs except AZT (161,162). A recent study, in which T69 deletions were replaced with the wildtype threonine residue, suggested that their phenotypic effect is minimal (163). K70 deletions have in vitro effects that appear to be similar to those of T69 deletions. An S68 deletion has been reported to emerge during in vitro passage with an investigational NRTI and to have in vitro effects that are also similar to T69 deletions (164).
T69D is a nonpolymorphic NRTI-selected mutation that primarily reduces susceptibility to ddI and possibly d4T (165,166,11,167,168). T69N is a somewhat nonpolymorphic NRTI-selected mutation. In combination with TAMs, it appears to contribute reduced susceptibility to AZT, ddI and d4T (169) T69G is a rare nonpolymorphic mutation that usually occurs in viruses from patients with a D67 deletion (160).
V75T/M/A/S are nonpolymorphic NRTI-selected mutations (135). V75T is selected primarily by d4T and ddI and reduces susceptibility to these NRTIs (170,4,81). V75M is selected in patients receiving a regimen containing d4T and 3TC, particularly in CRF01_AE viruses (171,54). It appears to reduce susceptibility to ddI, d4T, and possibly AZT. Few data are available on the significance of V75S/A.
N348I is a nonpolymorphic accessory mutation selected by the NRTIs AZT and d4T and by the NNRTIs NVP and EFV (172,173,174). Alone, it reduces AZT susceptibility about 3-fold and NVP and EFV susceptibility by 3-fold and 2-fold, respectively (172,173,175,176). It facilitates primer unblocking by reducing the rate of RNA template degradation (172).
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