HBV Drug Resistance Substitutions Existed before the Clinical Approval of Nucleos(t)ide Analogues: A Bioinformatic Analysis by GenBank Data Mining
Abstract
:1. Introduction
2. Materials and Methods
2.1. Sequence Search and Qualification Strategy
2.2. Data Extraction
2.3. HBV Genotyping and Detection of Recombinant Sequences
2.4. Systematic Analysis of Potential NUCr Substitutions
2.5. HBV Drug Resistance Substitution Analysis
2.6. Statistical Analysis
3. Results
3.1. Selection for RT-Containing HBV Sequences
3.2. Quality Control for HBV RT-Containing Sequences
3.3. RT Sequence Origins and HBV Genotypes
3.4. NUCr Substitution Analysis
3.5. Characterization of the RT Sequences Harboring AA Substitutions Associated with NUCr
4. Discussion
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Drugs | Primary NUCr Substitutions | Secondary Substitutions |
---|---|---|
LAM | rtA181T/V [2,4,11], rtA181S [27], rtM204I/V [2,4,11], rtM204Q/S [28,29] | rtH55R [30], rtL80I/V [2,4,11], rtS117F [31], rtT128N [32], rtW153Q [32], rtV173L [2,4,11], rtL180M [2,4,11], rtL180C [33], rtA200V [34], rtV207I [35], rtL217P [36], rtL229F [37], rtQ267H [38], rtL269I [39] |
ADV | rtS78T [40], rtA181T/V [2,4,11], rtA181S [41], rtE218G [42], rtI233V [43], rtN236T [2,4,11], rtN236V [44] | rtL80I/V [45], rtV84M [46], rtS85A [46], rtV214A [47], rtL217R [48], rtP237H [47] |
ETV | rtS78T [18], rtI169T [2,4,11], rtA181T/V [2,4,11], rtT184A/C/F/G/I/L/M/S [2,4,11], rtA186T [17], rtS202C/G/I [2,4,11], rtM204I/V [2,4,11], rtM250I/V/L [2,4,11] | rtI163V [17], rtS219A [49], rtY245H [49], rtS246T [50], rtL269I [39] |
LdT | rtM204I/V [2,4,11], rtA181T/V [2,4,11] | |
TDF/TAF | rtS78T [18], rtP177G [51], rtA181T/V [2,4,11], rtA194T [2,4,11], rtF249A [51] |
Substitution Category | NUCr-Related Codons | Substitution Types | No. of Substituted AAs | No. of Available AAs | Substitution Frequency (%) 1 |
---|---|---|---|---|---|
Primary | rtI169 | L | 2 | 366 | 0.5 |
NUCr | rtA181 | G | 1 | 355 | 0.3 |
substitution | rtT184 | A 3, S 3 | 1, 1 | 355 | 0.6 |
rtA194 | ND | 0 | 332 | 0 | |
rtS202 | T, R | 2, 1 | 325 | 0.9 | |
rtM204 | L | 2 | 324 | 0.6 | |
rtN236 | ND | 0 | 155 | 0 | |
rtM250 | K | 1 | 138 | 0.7 | |
Subtotal | 8 codons | 6 codons, 8 types | 11 | 2350 | 0.5 2 |
Secondary | rtL80 | V 3 | 7 | 288 | 2.4 |
substitution | rtV173 | G, A, L 3 | 5, 2, 2 | 366 | 2.5 |
rtL180 | ND | 0 | 355 | 0 | |
Subtotal | 3 codons | 2 codons, 4 types | 16 | 1008 | 1.6 2 |
Total | 11 codons | 8 codons, 12 types | 27 | 3358 | 0.8 |
Accession Number | Releasing Year | Sample Origin | Sequencing Method | Sequence Length (bp) | RT Coverage (AA) | Genotype | Substitution | References |
---|---|---|---|---|---|---|---|---|
X01587.1 | 1983 | Japan | Clone | 3214 | 1–344 | C | V173G | [58] |
M23808.1 | 1985 | Japan | Clone | 681 | 10–235 | C | V173G | [59] |
E01164.1 | 1986 | Japan | Clone | 748 | 6–253 | C | V173G | NA |
M38636.1 | 1988 | South Korea | Clone | 3213 | 1–344 | C | V173G | [60] |
U19777.1 | 1988 | China | Clone | 731 | 1–243 | C | T184A | NA |
M27765.1 | 1989 | Japan | Clone | 678 | 10–234 | C | I169L | [61] |
X14193.1 | 1989 | South Korea | Clone | 3213 | 1–344 | C | V173G | [62] |
S50225.1 | 1992 | USA | Clone | 3222 | 1–344 | A | V173A | [63] |
S56208.1 | 1992 | India | Clone | 123 | 169–208 | D | S202T | [64] |
X77310.1 | 1994 | Italy | Direct | 1401 | 1–300 | D | S202R | NA |
X80925.1 | 1995 | UK | Direct | 3182 | 1–344 | D | S202T | [65] |
D50519.1 | 1996 | Japan | Clone | 3215 | 1–344 | C | A181G | [66] |
AF013631.1 | 1997 | China | Clone | 681 | 10–235 | C | L80V | [67] |
AF036236.1 | 1997 | China | Clone | 838 | 1–236 | C | L80V | NA |
AF036237.1 | 1997 | China | Clone | 838 | 1–236 | C | L80V | NA |
AF036238.1 | 1997 | China | Clone | 838 | 1–236 | C | L80V | NA |
AF036239.1 | 1997 | China | Clone | 838 | 1–236 | C | L80V | NA |
U87739.1 | 1997 | South Africa | Direct | 846 | 1–235 | A | L80V | [68] |
AB014382.1 | 1998 | Japan | Direct | 3215 | 1–344 | C | L80V | [69] |
AJ003027.1 | 1998 | Germany | Clone | 1158 | 1–235 | D | I169L | [70] |
AF043564.1 | 1998 | Argentina | Direct | 217 | 122–193 | A | V173A | [71] |
AJ003026.1 | 1998 | Germany | Clone | 1164 | 1–235 | D | V173L | [70] |
AJ003028.1 | 1998 | Germany | Clone | 1164 | 1–235 | D | V173L | [70] |
AF044985.1 | 1998 | Belgium | Clone | 297 | 117–215 | B | T184S | NA |
AF074449.1 | 1998 | Thailand | Direct | 720 | 10–248 | C | M204L | [72] |
AF075604.1 | 1998 | Thailand | Direct | 720 | 10–248 | C | M204L | NA |
AJ012207.1 | 1998 | Germany | Clone | 3221 | 1–344 | A | M250K | NA |
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Xu, X.; Xiang, K.; Su, M.; Li, Y.; Ji, W.; Li, Y.; Zhuang, H.; Li, T. HBV Drug Resistance Substitutions Existed before the Clinical Approval of Nucleos(t)ide Analogues: A Bioinformatic Analysis by GenBank Data Mining. Viruses 2017, 9, 199. https://doi.org/10.3390/v9080199
Xu X, Xiang K, Su M, Li Y, Ji W, Li Y, Zhuang H, Li T. HBV Drug Resistance Substitutions Existed before the Clinical Approval of Nucleos(t)ide Analogues: A Bioinformatic Analysis by GenBank Data Mining. Viruses. 2017; 9(8):199. https://doi.org/10.3390/v9080199
Chicago/Turabian StyleXu, Xizhan, Kuanhui Xiang, Mingze Su, Yao Li, Wei Ji, Yutang Li, Hui Zhuang, and Tong Li. 2017. "HBV Drug Resistance Substitutions Existed before the Clinical Approval of Nucleos(t)ide Analogues: A Bioinformatic Analysis by GenBank Data Mining" Viruses 9, no. 8: 199. https://doi.org/10.3390/v9080199