Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase.
Emergence of drug-resistance to all FDA-approved antiherpesvirus agents is an increasing concern in immunocompromised patients. Herpesvirus DNA polymerase (DNApol) is currently the target of nucleos(t)ide analogue-based therapy. Mutations in DNApol that confer resistance arose in immunocompromised patients infected with herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV), and to lesser extent in herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6). In this review, we present distinct drug-resistant mutational profiles of herpesvirus DNApol. The impact of specific DNApol amino acid changes on drug-resistance is discussed. The pattern of genetic variability related to drug-resistance differs among the herpesviruses. Two mutational profiles appeared: one favoring amino acid changes in the Palm and Finger domains of DNApol (in α-herpesviruses HSV-1, HSV-2 and VZV), and another with mutations preferentially in the 3'-5' exonuclease domain (in β-herpesvirus HCMV and HHV-6). The mutational profile was also related to the class of compound to which drug-resistance emerged.
Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium dimitrios.topalis@rega.kuleuven.be.
D
D
Topalis
Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium.
S
S
Gillemot
Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium.
R
R
Snoeck
Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium graciela.andrei@rega.kuleuven.be.
G
G
Andrei
D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D017124:Conserved Sequence; D004256:DNA Polymerase I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D024882:Drug Resistance, Viral; D004789:Enzyme Activation; D019143:Evolution, Molecular; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006564:Herpesviridae / Q000145:classification / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009154:Mutation; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D000998:Antiviral Agents; D014764:Viral Proteins; D004256:DNA Polymerase I; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus
J Clin Virol. 2009 Jan;44(1):15-9
18952495
J Gen Virol. 2014 Apr;95(Pt 4):940-7
24413420
Virology. 1998 Sep 1;248(2):382-93
9721246
J Antimicrob Chemother. 1993 Jul;32 Suppl A:121-32
8407694
Apoptosis. 2011 Mar;16(3):256-71
21107701
J Mol Biol. 2011 Sep 2;411(5):999-1016
21723875
Antivir Ther. 2004 Feb;9(1):97-104
15040541
N Engl J Med. 2013 Sep 26;369(13):1227-36
24066743
Antimicrob Agents Chemother. 2015;59(6):3140-8
25779572
Biochim Biophys Acta. 1981 Jan 29;652(1):90-8
6260189
Antiviral Res. 2004 Mar;61(3):181-7
15168799
J Clin Virol. 2013 Jan;56(1):19-24
23026414
J Biol Chem. 2009 Jun 19;284(25):16784-90
19411250
Clin Pharmacol Ther. 2015 Jan;97(1):66-78
25670384
Adv Enzyme Regul. 1985;24:377-84
3012971
Adv Pharmacol. 2013;67:107-68
23886000
World J Gastroenterol. 2014 Aug 21;20(31):10658-67
25152570
Comput Struct Biotechnol J. 2015 Feb 10;13:153-9
25750703
Antimicrob Agents Chemother. 2011 Feb;55(2):459-72
21078929
Mol Pharmacol. 1984 Sep;26(2):376-80
6090888
N Engl J Med. 2014 Jan 16;370(3):201-10
24428466
J Virol. 1994 Aug;68(8):4963-72
8035495
Clin Microbiol Rev. 2010 Oct;23(4):689-712
20930070
Bioorg Med Chem. 2000 Mar;8(3):601-15
10732977
PLoS One. 2015 Dec 02;10(12):e0143947
26630264
J Virol. 2012 Oct;86(20):11057-65
22875965
Antimicrob Agents Chemother. 1998 Aug;42(8):2095-102
9687413
Antimicrob Agents Chemother. 2013 Mar;57(3):1339-46
23274658
Chem Biol. 2004 May;11(5):647-54
15157875
J Biol Chem. 2011 Jul 15;286(28):25246-55
21566148
Antimicrob Agents Chemother. 2010 Aug;54(8):3093-8
20547817
J Virol. 1994 Aug;68(8):4937-45
8035492
DNA Repair (Amst). 2015 May;29:36-46
25753811
J Virol. 2013 Apr;87(7):3930-42
23365421
Biochemistry. 1997 May 6;36(18):5336-45
9154915
Antiviral Res. 2015 Mar;115:17-20
25542973
J Virol. 1990 Dec;64(12):5976-87
2173776
J Virol. 2012 Mar;86(5):2641-52
22190713
N Engl J Med. 2014 Apr 24;370(17):1663-4
24758629
Biochemistry. 2001 May 29;40(21):6344-51
11371196
Med Res Rev. 2012 Jul;32(4):765-85
22581627
Vaccine. 2011 Nov 3;29(47):8530-41
21767588
Biochim Biophys Acta. 1982 Feb 26;696(2):115-23
6277381
J Neurovirol. 2013 Aug;19(4):346-50
23775137
Clin Med Insights Womens Health. 2014 Feb 13;7:1-8
24741339
Bioorg Med Chem Lett. 2000 Sep 18;10(18):2079-81
10999475
J Virol. 2006 Feb;80(3):1440-50
16415021
Biochim Biophys Acta. 1980 Mar 28;607(1):53-64
6245699
J Gen Virol. 1984 Mar;65 ( Pt 3):467-75
6321635
Antiviral Res. 1981 Nov;1(4):203-12
6280605
J Virol. 2005 May;79(9):5863-9
15827202
J Infect Dis. 2015 Dec 15;212(12 ):1949-56
26044291
Ther Clin Risk Manag. 2014 Sep 05;10:721-36
25228810
Expert Opin Investig Drugs. 2000 Aug;9(8):1743-51
11060773
J Virol. 2004 Feb;78(4):1893-902
14747554
Biochemistry. 2016 Feb 23;55(7):1168-77
26836009
Eur J Biochem. 1990 Jul 5;190(3):463-7
2164928
Viruses. 2013 Jan 08;5(1):54-86
23299784
Infect Disord Drug Targets. 2011 Oct;11(5):504-13
21827431
J Virol. 2014 Oct;88(19):11121-9
25008933
Nucleic Acids Res. 2014 Dec 16;42(22):14013-21
25429975
Antimicrob Agents Chemother. 2003 May;47(5):1707-13
12709344
Antivir Ther. 2007;12(5):719-32
17713155
Pediatr Infect Dis J. 2001 Nov;20(11):1083-6
11734717
Clin Infect Dis. 1994 Apr;18(4):570-8
8038312
J Biol Chem. 1984 Aug 10;259(15):9575-9
6086640
Antivir Ther. 2010;15(4):579-86
20587851
N Engl J Med. 2014 May 8;370(19):1781-9
24806159
Mutat Res. 2002 Dec 29;510(1-2):45-54
12459442
Ann Med. 1993 Oct;25(5):441-5
8251142
Adv Pharmacol. 2013;67:1-38
23885997
Future Virol. 2013 Dec 1;8(12):1151-1160
24465269
J Clin Virol. 2012 Jan;53(1):6-11
21889905
Curr Top Microbiol Immunol. 2008;325:361-82
18637516
J Infect Dis. 2012 Apr 1;205(7):1100-10
22351940
J Antimicrob Chemother. 2010 Aug;65(8):1733-41
20534624
Drugs. 2002;62(13):1853-8
12215056
J Virol. 2003 Jul;77(14):7820-9
12829822
J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):237-8
12185148
Expert Opin Biol Ther. 2014 Aug;14(8):1121-6
24762099
J Biol Chem. 2006 Jun 30;281(26):18193-200
16638752
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3475-80
25733891
J Gen Virol. 2000 Mar;81(Pt 3):639-48
10675401
Cell Host Microbe. 2011 Oct 20;10(4):379-89
22018238
J Virol. 2015 Apr;89(8):4636-44
25673718
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17462-7
25422422
J Clin Virol. 2015 Aug;69:150-5
26209398
J Gen Virol. 2001 Nov;82(Pt 11):2761-5
11602787
Int J Dermatol. 2014 Apr;53(4):397-403
24673253
Antimicrob Agents Chemother. 1988 Aug;32(8):1137-42
2847643
Antivir Ther. 2007;12(6):877-88
17926642
Curr Opin Infect Dis. 2011 Dec;24(6):605-11
22001948
J Virol. 2014 Jan;88(1):655-66
24173231
Biochim Biophys Acta. 1980 Sep 19;609(2):232-45
6250618
Nucleosides Nucleotides Nucleic Acids. 2008 Apr;27(4):319-31
18404568
Antimicrob Agents Chemother. 2012 May;56(5):2726-34
22391537
Rev Med Virol. 2002 May-Jun;12(3):167-78
11987142
J Med Virol. 2002 Oct;68(2):234-6
12210413
Antimicrob Agents Chemother. 1997 Mar;41(3):594-9
9055999
J Infect Dis. 2013 Apr 15;207(8):1295-305
23315323
Handb Exp Pharmacol. 2009;(189):53-84
19048197
Antimicrob Agents Chemother. 1992 Dec;36(12):2747-57
1336346
EBioMedicine. 2015 Aug 03;2(9):1018-9
26501093
J Virol. 1998 Jan;72(1):717-25
9420278
J Biol Chem. 2014 Jan 31;289(5):2888-98
24324256
J Virol. 2003 Feb;77(3):1868-76
12525621
Antimicrob Agents Chemother. 2011 Oct;55(10):4682-91
21788463
Expert Rev Anti Infect Ther. 2014 Oct;12(10):1171-8
25120093
J Virol. 2003 Aug;77(15):8336-44
12857903
Nature. 1996 Sep 19;383(6597):272-5
8805706
Int J Immunopathol Pharmacol. 2013 Jan-Mar;26(1):15-26
23527705
J Clin Microbiol. 1982 Apr;15(4):733-6
6279696
Antiviral Res. 2014 Jul;107:16-22
24747042
Biochemistry. 1997 Nov 18;36(46):14023-9
9369473
J Biol Chem. 1981 Nov 25;256(22):11447-51
6271750
J Virol. 2015 Jan;89(1):241-8
25320299
Biochemistry. 2014 Jul 22;53(28):4648-60
24977643
Biochemistry. 2014 May 6;53(17):2752-67
24720884
N Engl J Med. 2014 Jan 16;370(3):273-4
24428473
Antimicrob Agents Chemother. 2010 Mar;54(3):1290-7
20047911
J Mol Biol. 1993 Dec 5;234(3):910-2
8254688
Antimicrob Agents Chemother. 2007 Jan;51(1):89-94
17043128
Antiviral Res. 2008 Mar;77(3):237-40
18241936
Semin Cancer Biol. 2014 Jun;26:60-8
24457012
Protein Expr Purif. 1997 Nov;11(2):209-18
9367818
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16802-7
24082122
J Clin Virol. 2008 Sep;43(1):107-9
18502683
J Biol Chem. 2010 Sep 3;285(36):27664-72
20601642
J Infect Dis. 1998 Dec;178(6):1821-5
9815243
J Virol. 2015 Jul;89(13):6673-84
25878109
J Biol Chem. 2015 Mar 27;290(13):8028-38
25666608
Virus Genes. 1998;16(1):85-93
9562893
Biochem Pharmacol. 2011 Jan 1;81(1):43-9
20846508
Curr Opin Infect Dis. 2015 Dec;28(6):589-95
26524331
Clin Infect Dis. 1998 Feb;26(2):512-3
9502489
Biochemistry. 1995 Feb 28;34(8):2504-10
7873530
Med Microbiol Immunol. 2015 Jun;204(3):255-62
25794555
J Virol. 2001 Oct;75(19):9077-86
11533171
N Engl J Med. 2015 Aug 6;373(6):530-9
26244306
Mol Pharmacol. 1992 Jan;41(1):197-202
1310143
Nature. 1994 Dec 15;372(6507):695-8
7990963
Antimicrob Agents Chemother. 2016 May 23;60(6):3845-8
27044553
Antimicrob Agents Chemother. 1985 Apr;27(4):445-8
2988429
J Infect Dis. 2016 Jan 1;213(1):23-30
26113373
EBioMedicine. 2015 Jul 09;2(9):1145-52
26501112
J Invest Dermatol. 1984 Jul;83(1 Suppl):29s-41s
6330219
Mol Pharmacol. 1981 Jul;20(1):230-3
6270535
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):447-52
9892653
Drug Des Discov. 1997 May;15(1):3-15
9332827
Int J Epidemiol. 1997 Aug;26(4):698-709
9279600
Biochemistry. 2000 Oct 24;39(42):12796-803
11041844
Virology. 1988 Sep;166(1):262-4
2842952
J Pathol. 2015 Jan;235(2):288-97
25205255
J Mol Biol. 2002 Nov 15;324(1):89-103
12421561
Antiviral Res. 2013 Feb;97(2):154-60
23261844
Mol Pharmacol. 1991 Oct;40(4):591-6
1656194
Antimicrob Agents Chemother. 2014 Dec;58(12):7312-23
25267682
Antimicrob Agents Chemother. 2014;58(4):2329-33
24514084
J Gen Virol. 1986 Aug;67 ( Pt 8):1625-32
3016157
Biochem Pharmacol. 1996 Jun 14;51(11):1563-7
8630098
Nat Rev Microbiol. 2014 Mar;12(3):197-210
24509782
Haematologica. 2008 May;93(5):e39-41
18450727
J Am Chem Soc. 2011 Feb 23;133(7):2264-74
21280608
Antiviral Res. 2012 Feb;93(2):301-4
22155691
Curr Neurol Neurosci Rep. 2013 Dec;13(12):414
24142852
Antiviral Res. 2002 Apr;54(1):19-28
11888654
J Med Chem. 2005 Sep 8;48(18):5794-804
16134946
J Virol. 1985 Mar;53(3):776-80
2983088
Biochem Pharmacol. 2004 Dec 15;68(12):2301-15
15548377
Antimicrob Agents Chemother. 2013 Sep;57(9):4343-8
23817384
J Clin Virol. 2013 Feb;56(2):175-6
23177166
J Biol Chem. 1984 Feb 10;259(3):1566-9
6319402
DNA Repair (Amst). 2002 Jan 22;1(1):59-75
12509297
J Virol. 2004 Jan;78(1):158-67
14671097
Virulence. 2010 Nov-Dec;1(6):555-7
21178503
Med Res Rev. 2005 Jan;25(1):1-20
15389733
Mol Pharmacol. 1982 Mar;21(2):432-7
6285172
Sci Rep. 2015 Jun 30;5:11767
26123572
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):2874-9
9096314
Cancer Lett. 2011 Jun 28;305(2):163-74
21493001
Curr Opin Investig Drugs. 2008 Feb;9(2):132-45
18246516
Antimicrob Agents Chemother. 2012 Jan;56(1):197-201
21968367
FASEB J. 2013 Jul;27(7):2584-99
23507869
Proc Natl Acad Sci U S A. 1981 May;78(5):2698-702
6265902
Vaccine. 2011 Nov 3;29(47):8520-9
21945262
J Pathol. 2015 Jan;235(2):312-22
25294567
Viruses. 2010 Dec;2(12):2740-2762
21499452
Antimicrob Agents Chemother. 2002 Aug;46(8):2365-72
12121906
Antimicrob Agents Chemother. 2012 Jul;56(7):3587-91
22526302
Infect Drug Resist. 2015 Aug 05;8:269-77
26345608
Clin Transl Immunology. 2015 Feb 27;4(2):e33
25774295
Infect Disord Drug Targets. 2009 Apr;9(2):201-22
19275707