Free accessArticle commentaryFirst published online 2011-10
Article Commentary: A Structural Frame for Understanding the Role of Thymidine Analogue Resistance Mutations in Resistance to Zidovudine and Other Nucleoside Analogues
The acquisition of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) can be mediated by amino acid changes at the dNTP binding site that affect the catalytic efficiency of nucleotide analogue incorporation, or by mutations that, in the presence of a pyrophosphate donor, facilitate excision of 3'-terminal chain-terminating inhibitors from blocked primers. These mutations, known as thymidine analogue resistance mutations (TAMs) are M41L, D67N, K70R, L210W, T215F/Y and K219E/Q. Recently published crystal structures of wild-type and TAM-containing HIV-1 reverse transcriptases bound to double-stranded DNA and the excision product, azidothymidine adenosine dinucleoside tetraphosphate have shed light into the molecular mechanism of excision.
References
1.
De ClercqE.Antiretroviral drugs. Curr Opin Pharmacol2010; 10: 507–515.
2.
Menéndez-AriasL.Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res2008; 134: 124–146.
3.
SarafanosS.G., DasK., ClarkA.D.Jr.. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with β-branched amino acids. Proc Natl Acad Sci U S A1999; 96: 10027–10032.
4.
ArionD., KaushikN., McCormickS., BorkowG., ParniakM.A.Phenotypic mechanism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry1998; 37: 15908–15917.
5.
MeyerP.R., MatsuuraS.E., MianA.M., SoA.G., ScottW.A.A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell1999; 4: 35–43.
6.
MarchandB., GötteM.Impact of the translocational equilibrium of HIV-1 reverse transcriptase on the efficiency of mismatch extensions and the excision of mispaired nucleotides. Int J Biochem Cell Biol2004; 36: 1823–1835.
7.
DharmasenaS., PongraczZ., ArnoldE., SarafanosS.G., ParniakM.A.3′-Azido-3′-deoxythymidine-(5')-tetraphospho-(5')-adenosine, the product of ATP-mediated excision of chain-terminating AZTMP, is a potent chain-terminating substrate for HIV-1 reverse transcriptase. Biochemistry2007; 46: 828–836.
8.
HuangH., ChopraR., VerdineG.L., HarrisonS.C.Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science1998; 282: 1669–1675.
9.
SarafanosS.G., ClarkA.D.Jr., DasK.Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J2002; 21: 6614–6624.
10.
BoyerP.L., SarafanosS.G., ArnoldE., HughesS.H.Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol2001; 75: 4832–4842.
11.
TuX., DasK., HanQ.Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol2010; 17: 1202–1209.
12.
LaceyS.F., ReardonJ.E., FurfineE.S.Biochemical studies on the reverse transcriptase and RNase H activities from human immunodeficiency virus strains resistant to 3′-azido-3′-deoxythymidine. J Biol Chem1992; 267: 15789–15794.
13.
BoyerP.L., SarafanosS.G., ArnoldE., HughesS.H.Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision. J Virol2002; 76: 9143–9151.
14.
MatamorosT., FrancoS., Vázquez-álvarezB.M., MasA., MartínezM.A., Menéndez-AriasL.Molecular determinants of multi-nucleoside analogue resistance in HIV-1 reverse transcriptases containing a dipeptide insertion in the fingers subdomain – effect of mutations D67N and T215Y on removal of thymidine nucleotide analogues from blocked DNA primers. J Biol Chem2004; 279: 24569–24577.
15.
Cases-GonzálezC.E., FrancoS., MartínezM.A., Menéndez-AriasL.Mutational patterns associated with the 69 insertion complex in multi-drug-resistant HIV-1 reverse transcriptase that confer increased excision activity and high-level resistance to zidovudine. J Mol Biol2007; 365: 298–309.
16.
KisicM., MatamorosT., NevotM.Thymidine analogue excision and discrimination modulated by mutational complexes including single amino acid deletions of Asp-67 or Thr-69 in HIV-1 reverse transcriptase. J Biol Chem2011; 286: 20615–20624.
17.
VillenaC., PradoJ.G., PuertasM.C.Relative fitness and replication capacity of a multinucleoside analogue-resistant clinical human immunodeficiency virus type 1 isolate with a deletion of codon 69 in the reverse transcriptase coding region. J Virol2007; 81: 4713–4721.
18.
KisicM., MendietaJ., PuertasM.C.Mechanistic basis of zidovudine hypersusceptibility and lamivudine resistance conferred by the deletion of codon 69 in the HIV-1 reverse transcriptase coding region. J Mol Biol2008; 382: 327–341.
19.
Cozzi-LepriA., RuizL., LovedayC.Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy. Antivir Ther2005; 10: 791–802.
20.
JeeningaR.E., KeulenW., BoucherC., SandersR.W., BerkhoutB.Evolution of AZT resistance in HIV-1: the 41–70 intermediate that is not observed in vivo has a replication defect. Virology2001; 283: 294–305.
