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.

NRTI Resistance Notes

Last updated on March 2, 2014
Major Nucleoside RT Inhibitor (NRTI) Resistance Mutations
 
         Discriminatory Mutations   Thymidine Analog Mutations (TAMs)   MDR Mutations
  184 65 70 74 115   41 67 70 210 215 219   69 151
Consensus M K K L Y   M D K T T K   T Q
3TC VI R                       Ins M
FTC VI R                       Ins M
ABC VI R E VI F   L     W FY     Ins M
DDI VI R E VI     L     W FY     Ins M
TDF ***   E   F   L   R W FY     Ins M
D4T *** R E       L N R W FY QE   Ins M
ZDV *** *** * *     L N R W FY QE   Ins M
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


M184V is selected by 3TC/FTC and reduces susceptibility to these drugs >100-fold. It is also selected by, and causes low-level resistance to, ABC and ddI (1,2,3,4,5,6,7,8,9,10,11,12,13,14). In contrast, M184V increases susceptibility to AZT, d4T and TDF (15,16,17,18,3,19,4,5,13,20) and slows the emergence of AZT, d4T, and TDF resistance (21,22,23,16,24,25,26,27,28,26,29). M184V is also associated with reduced viral replication in vitro and in vivo (30,31,32,33,31,34,35,36). A combination of TDF, AZT or d4T plus 3TC/FTC often partially inhibits viruses with M184V.

M184I usually emerges before M184V because it results from a more common HIV-1 nucleotide substitution (37). However, M184V outcompetes M184I within several weeks of viral replication and is found in most patients with virological failure on 3TC or FTC (37,30). M184I/V have similar resistance profiles (5,38,39).


Thymidine Analog Mutations (TAMs)


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) (40,41,42,43,44,45,46). The classical TAMs - M41L, D67N, K70R, L210W, T215Y/F and K219Q/E - were first reported in patients receiving AZT monotherapy (47,48,49,50). 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 decreased NRTI susceptibility.

TAM patterns
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 (29,51,52,53,54). Type 1 TAMs have a greater negative impact on virological response to an ABC-, ddI-, or TDF-containing regimen than do Type 2 TAMs (8,11,7,55,29,56,57). 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.

Individual TAMs
(i) M41L usually occurs in combination with T215Y. Together, M41L and T215Y confer high-level resistance to AZT and d4T and 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.

T215 revertants
Patients primarily infected with strains containing T215Y/F often develop viruses with the following reversion mutations (58,59,60): T215C/D, from the mutation of TAT (Y) to TGT (C) or GAT (D); T215I/V, from the mutation of TTT (F) to ATT (I) or GTT (V); T215S (TCT) from mutation of either TAT (Y) or TTT (F). T215E requires one change from T215D. T215S/C/D/E do not reduce NRTI susceptibility. Phenotypic data are not available for T215I/V. T215 revertants are among the most commonly reported transmitted drug resistance mutations (60,61,62). Some, but not most, ARV-naive patients with T215 revertants may be at higher risk of developing virological failure on first-line regimens with a low genetic barrier to resistance (63,64,65,66).

Variants at TAM positions
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 (67,68,4). In contrast to K70R, K70E/G/Q increase susceptibility to AZT and decrease susceptibility to the remaining NRTIs (69,70,71,72).

Accessory TAMs
E40F, E44D/A and V118I contribute to reduced NRTI susceptibility primarily in combination with other TAMs (73,74,75,76,77,4). V118I is polymorphic and occurs in 2% to 3% of ARV-naive patients; E40F and E44D/A are nonpolymorphic. E43Q/N, K64R, E203K, H208Y, D218E, K223Q/E and L228H/R are poorly characterized nonpolymorphic NRTI-selected mutations that occur in combination with other TAMs (78,79,68).

N348I
N348I is a nonpolymorphic accessory mutation selected by the NRTIs AZT and d4T and by the NNRTIs NVP and EFV (80,81,82). Alone, it reduces AZT susceptibility about 3-fold and NVP and EFV susceptibility by 3-fold and 2-fold, respectively (80,81,83,84). It facilitates primer unblocking by reducing the rate of RNA template degradation (80).



Non-TAMs

K65R/N/E
K65R is selected by TDF, ABC, d4T and ddI (69,85,86) (87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102). It reduces TDF, ABC and ddI susceptibility ~2-fold (4,103,38,6,71), d4T susceptibility ~1.5-fold, and 3TC/FTC susceptibility 5 to 10-fold (99). Together K65R and M184V are sufficient (in the absence of other NRTI-resistance mutations) to cause virological failure in patients receiving non-AZT-containing dual NRTI-containing regimens. K65R increases AZT susceptibility, except when it occurs in combination with Q151M (4,103,104,105,21,5,6,106,107,108,4).

K65N is an uncommon NRTI-selected mutation that reduces susceptibility to TDF, 3TC/FTC, ABC and ddI (109,110,39). It has been reported primarily in patients receiving d4T or TDF plus 3TC/FTC (98,111,112,113). It also appears to increase susceptibility to AZT (110). K65E is an extremely rare, highly unfit NRTI-selected mutation (114) that usually occurs as part of an electrophoretic mixture with the wildtype K (71).


T69D/N/G
T69D is a nonpolymorphic NRTI-selected mutation that primarily reduces susceptibility to ddI and possibly d4T (115,116,11,117,118). T69N is a nonpolymorphic NRTI-selected mutation reported to reduce susceptibility to AZT, ddI and d4T (119) T69G is a rare nonpolymorphic mutation that usually occurs in viruses from patients with a D67 deletion (120).


K70E/G/Q/T/N/S
K70E/G are an uncommon mutations selected in patients receiving d4T-, TDF- and ABC-containing regimens (121,122,123,93,92,124,125,126). They modestly reduce susceptibility to these NRTIs, cause potential low-level resistance to 3TC/FTC, and increase AZT susceptibility (69,70,71). K70Q/T/N/S are rare nonpolymorphic NRTI-selected mutations that may have phenotypic effects similar to K70E/G (127,72).

L74V/I
L74V is selected by ABC and ddI. Together, L74V and M184V are the most common mutations to develop in patients receiving ABC/3TC (86,128,101,94,6). In combination, they reduce 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 (128,129,130,4,13,131). In contrast, TDF treatment does not select against L74V even though this mutation increases susceptibility to TDF in vitro (132,130).

L74I is selected primarily by ddI and ABC, and occasionally by TDF (133,134,67,111). It is less effective than L74V in reducing susceptibility to ABC and ddI. It does not appear to significantly increase AZT and TDF susceptibility (67).

V75T/M/A/S
V75T/M/A/S are nonpolymorphic NRTI-selected mutations (127). V75T is selected primarily by d4T and ddI and reduces susceptibility to these NRTIs (135,4,39). V75M is selected in patients receiving a regimen containing d4Tand 3TC, particularly in CRF01_AE viruses (136,98). It appears to have a similar but less pronounced phenotypic effect than V75T on d4T, ddI and ABC. Few data are available on the significance of V75S/A.

Y115F
Y115F is selected by ABC and TDF (86,110,137,110,1,138,95,3,91,92,93,111). 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 (38,110,4).


Multi-Nucleoside RT Inhibitor Resistance Mutations

Q151M Complex
Q151M usually occurs in combination with two or more of the following four accessory mutations: A62V, V75I, F77L, and F116Y. 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. Q151L is an extremely rare nonpolymorphic NRTI-selected mutation representing a transition between wildtype and Q151M. It does not appear to reduce NRTI susceptibility (139).


Beta3-Beta4 Insertions and Deletions
Beta3-Beta4 insertions are by convention assigned to position 69. These insertions usually comprise a T69S substitution followed by two additional amino acids (140,141,142,143). 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.

The most common Beta3-Beta4 deletions occur at positions 67 and 69. Position 67 deletions usually occur in combination with the unusual mutation T69G and either Q151M or multiple TAMs (144,120,145). Viruses with position 67 mutations usually have high-level reductions in susceptibility to to most NRTIs. T69 deletions usually occur in combination with K65R and/or Q151M (98). Viruses with T69 deletions plus K65R alone exhibit reduced susceptibility to all NRTIs except AZT (145,146,147)

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