Table 4.
HIV-1 Nucleoside RT Inhibitor (NRTI) Drug-Resistance Mutations
| Codon | Mechanism | Effect on Resistance1 | References |
|---|---|---|---|
| 41 | Classical AZT2 | M41L increases AZT resistance when present with T215Y/F. | Kellam et al., 1992; Larder et al., 1994 |
| 44 | Accessory5 | E44A/D occurs with increased frequency in patients receiving multiple NRTI. It has recently been shown to cause low-level 3TC resistance when present with V118I. | Delaugerre et al., 2001; Hertogs et al., 2000a |
| 62 | MNR4 | A62V is associated with multinucleoside resistance caused by Q151M. | Iversen et al., 1996; Shirasaka et al., 1995b |
| 65 | β2-β3 loop region3 | K65R causes high-level resistance to DDC and low-to-intermediate levels of resistance to ddI, ABC, and 3TC. | Gu et al., 1994a; Gu et al., 1994b; Tisdale et al., 1997; Zhang et al., 1994 |
| 67 | Classical AZT,2 β2-β3 loop region 3 | D67N contributes to AZT resistance usually with mutations at codons 70 or 215. D67E/G occurs in heavily treated patients. | Larder and Kemp, 1989 |
| 69 | β2-β3 loop region3 | T69D/N/A cause ddC and ddI resistance and may cause low-level D4T resistance particularly when present in isolates with classical AZT resistance mutations. Insertions at this codon are by themselves associated with low level resistance to each of the NRTI. Together with AZT resistance mutations, insertions are associated with moderate-to-high levels of resistance to AZT, ddI, ddC, d4T, and 3TC. | Bloor et al., 1998; Fitzgibbon et al., 1992; Hertogs et al., 1998; Winters et al., 1998; Tamalet et al., 1998; Winters et al., 2001 |
| 70 | Classical AZT,2 β2-β3 loop region3 | K70R causes AZT resistance. | Larder and Kemp, 1989; de Jong et al., 1996, Shulman et al., 2001 |
| 74 | β2-β3 loop region3 | L74V causes ddI, ddC, and ABC resistance. L74V partially suppresses T215Y-mediated AZT resistance. | St. Clair et al., 1991; Tisdale et al., 1997; Kozal et al., 1994a |
| 75 | MNR4 | V75T/M/A causes d4T resistance and may cause low-level ddI and ddC resistance. V75I increases multinucleoside resistance caused by Q151M when present with F77L and F116Y. |
Lacey and Larder, 1994 Bloor et al., 1998; Iversen, et al., 1996; Shirasaka et al., 1995b |
| 77 | MNR4 | F77L increases multinucleoside resistance caused by Q151M when present with V75I or F116Y. | Iversen et al., 1996; Shirasaka et al., 1995b |
| 115 | Accessory5 | Y115F causes low-level resistance to ABC. | Tisdale et al., 1997 |
| 116 | MNR4 | F116Y increases multinucleoside resistance caused by Q151M when present with F77L or V75I. | Iversen et al., 1996; Shirasaka et al., 1995b |
| 118 | Accessory5 | V118I occurs with increased frequency in patients receiving multiple NRTI. It has recently been shown to cause intermediate 3TC resistance when present with E44A/D. | Delaugerre et al., 2001; Hertogs et al., 2000a |
| 151 | MNR4 | Q151M causes intermediate levels of resistance to AZT, ddI, ddC, d4T, and ABC. Q151M, together with its associated changes at codons 62, 75, 77, and 116 causes high-level resistance to these NRTI and low-level resistance to 3TC. | Iversen et al., 1996; Schmit et al., 1998; Shafer et al., 1994; Shirasaka et al., 1995b; Van Laethem et al., 2000 |
| 184 | Close to active site3 | M184V/I cause high-level 3TC resistance and low-level ddI, ddC, and ABC resistance. M184V/I partially suppresses T215Y-mediated AZT resistance. | Boucher et al., 1993; Gu et al., 1992; Larder et al., 1995; Schuurman et al., 1995; Tisdale et al., 1997; Tisdale et al., 1993 |
| 210 | Classical AZT2 | L210W increases AZT resistance when present with mutations at position 215. | Harrigan et al., 1996; Hooker et al., 1996 |
| 215 | Classical AZT2 | T215Y/F causes AZT resistance and also limits the effectiveness of d4T, ABC, ddI, and ddC. T215S/C/D represent transitions between T and Y or F. | Kozal et al., 1993; Larder, et al., 1991; Larder and Kemp, 1989; Rey et al., 1998; Yerly et al., 1998; Japour et al., 1998; Lanier et al., 1998; Izopet et al., 1998 |
| 219 | Classical AZT2 | K219Q/E increase AZT resistance when present with K70R or T215Y/F. K219N/R occur commonly in heavily NRTI-treated patients. | Larder and Kemp, 1989, Larder et al., 1991 |
3TC: lamivudine, ABC: abacavir, AZT: zidovudine, d4T: stavudine, ddI: didanosine, ddC: zalcitibine.
Classical AZT resistance mutations: Various combinations of these mutations have been shown to mediate ATP and pyrophosphate (PP)-dependent hydrolytic removal (pyrophosphorolysis) of zidovudine monophosphate from a terminated cDNA chain (Arion et al., 1998; Boyer et al., 2001; Meyer et al., 1999; Meyer et al., 1998; Meyer et al., 2000b), to cause a compensatory increase in RT processivity (Arion et al., 1998; Arts et al., 1998; Caliendo et al., 1996), and to confer cross-resistance to d4T, ABC, and limit the effectiveness of ddI and ddC (Coakley et al., 2000; Harrigan et al., 2000; Holodniy et al., 1996; Izopet et al., 1999; Japour et al., 1995; Lanier et al., 1999; Mayers et al., 1999; Montaner et al., 2000; Pellegrin et al., 1999; Shulman et al., 2001).
Mutations at position 184 and mutations in the β2-β3 loop region cause resistance by decreasing affinity of RT for the nucleoside analog. Several of these mutations, including M184V and L74V, interfere with the activity of the classical AZT resistance mutations.
MNR or multinucleoside resistance mutations: Q151M is the primary mutation. Mutations at positions 62, 75, 77, and 116 are secondary. Q151 possibly interacts directly with the 3′-OH of the incoming ddNTP (Sarafianos et al., 1999b).
Accessory: The combination of mutations at positions 44 and 118 have been shown to confer low-level 3TC resistance (Hertogs et al., 2000a). But the increasing prevalence of these mutations in isolates from heavily treated patients that also have classical AZT resistance mutations, suggests a broader role (Delaugerre et al., 2001). G333E is a polymorphism that facilitates AZT resistance in isolates with M184V and multiple classical AZT resistance mutations.