The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance
Abstract
:1. Introduction
Common name | Abbrev. | Structural name | Natural analog | Year FDA approved | Common resistance mutations selected b | Mechanism of resistance |
---|---|---|---|---|---|---|
zidovudine | ZDV, AZT | β-D-(+)-3′-azido-3′-deoxythymidine | dTTP | 1987 | M41L, D67N, K70R, L210W, T215F/Y, K219Q/E | excision |
didanosine | ddI | β-D-(+)-2′,3-dideoxyinosine | dATP | 1991 | K65R, L74V | discrimination |
stavudine | d4T | β-D-(+)-2′,3′-didehydro-3′-deoxythymidine | dTTP | 1994 | M41L, D67N, K70R, L210W, T215F/Y, K219Q/E | excision |
lamivudine | 3TC | β-L-(−)-2′,3′-dideoxy-3′-thiacytidine | dCTP | 1995 | K65R, M184V/I | discrimination |
abacavir | ABC | (1S,4R)-4-[2-amino-6-(cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate | dGTP | 1998 | K65R, L74V, Y115F, M184V | discrimination |
tenofovir c | TFV | ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)phosphonic acid | dATP | 2001 | K65R, K70E | discrimination |
emtricitabine | FTC | β-L-(−)-2′,3′-dideoxy-5-fluoro-3′-thiacytidine | dCTP | 2003 | K65R, M184V/I | discrimination |
2. Mutants of HIV-1 RT that Enhance the Rate of Nucleotide Excision
3. Mutations of HIV-1 RT that Decrease the Rate of Nucleotide Excision and Suppress AZT Resistance
Location in RT structure | How isolated? | Mutations | AZT sensitivity | Excision activity in vitro |
---|---|---|---|---|
dNTP binding site | Site-directed mutagenesis or bacterial library mutagenesis | D113G/E, A114S/G, Y115N/H, Q151H [66,70] R72A [71] | Hypersensitivity shown for D113E & A114S [70] | Reduced for A114S [72] |
From patients treated with NRTIs | K65R [73–76] | Suppression of AZT resistance [37,77–80] | Reduced for K65R [37,78] | |
Palm domain between the fingers domain and the template strand | From PFA-treated patients | W88S, W88G, Q161L, H208Y [68] | Suppression of AZT resistance shown for W88G and Q161L [37] No effect for W88S [37] | Reduced for W88G and Q161L [37] Not reduced for W88S [37] |
Serial passage of HIV-1 in culture | Q161L/H208Y [68] E89K, L92I, S156A [67] W88G, S117T, F160Y, M164I [76] | Suppression of AZT resistance shown for W88G, E89K, Q161L/H208Y, S117T, and M164I [37,67–69] | Reduced for W88G, E89K, Q161L/H208Y, S117T, and M164I [37] | |
Site-directed or random mutagenesis | K154E, Y183S, G190R [66,70,81] E89G/T/A/D/V[82,83] V90A [84] | AZT sensitivity not determined in infectivity assays | Not done |
4. Additional Mutations of HIV-1 RT that Suppress AZT Resistance (L74V, Y181C, L100I, V75I, M184V and K65R)
5. Indirect Enhancement of Excision due to Mutations in the RNase H and Connection Domains of RT
6. Conclusions
Acknowledgments
References
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Acosta-Hoyos, A.J.; Scott, W.A. The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance. Viruses 2010, 2, 372-394. https://doi.org/10.3390/v2020372
Acosta-Hoyos AJ, Scott WA. The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance. Viruses. 2010; 2(2):372-394. https://doi.org/10.3390/v2020372
Chicago/Turabian StyleAcosta-Hoyos, Antonio J., and Walter A. Scott. 2010. "The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance" Viruses 2, no. 2: 372-394. https://doi.org/10.3390/v2020372