Inhibition of HIV-1 reverse transcription: basic principles of drug action and resistance

References

• Morris MC, Berducou C, Mery J, Heitz F, Divita G. The thumb domain of the P51-subunit is essential for activation of HIV reverse transcriptase. Biochemistry 38, 15097–15103 (1999).
   PubMed Web of Science ®Google Scholar
• De Clercq E. Antiviral drugs in current clinical use. J. Clin. Viral. 30, 115–133 (2004).
   PubMed Web of Science ®Google Scholar
• •Timely review on currently used antiretrovirals and other antiviral drugs.
   Google Scholar
• Sarafianos SG, Clark AD Jr, Das K, et al. Structures of HIV-1 reverse transcriptase with pre-and post-translocation AZTMP-terminated DNA. EMBO J. 21,6614–6624 (2002).
   PubMedGoogle Scholar
• Krakow JS, Fronk E. Azotobacter vinelandii ribonucleic acid polymerase. 8. Pyrophosphate exchange. J. Biol. Chem. 244, 5988–5993 (1969).
   PubMedGoogle Scholar
• Marchand B, Götte M. Site-specific footprinting reveals differences in the translocation status of HIV-1 reverse transcriptase. Implications for polymerase translocation and drug resistance. J. Biol. Chem. 278, 35362–35372 (2003).
   PubMedGoogle Scholar
• Guajardo R, Sousa R. A model for the mechanism of polymerase translocation. J. Mol. Biol. 265, 8–19 (1997).
   PubMed Web of Science ®Google Scholar
• Boyer PL, Sarafianos SG, Arnold E, Hughes SH. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J. Viral. 75, 4832–4842 (2001).
   PubMed Web of Science ®Google Scholar
• Huang H, Chopra R, Verdine GL, Harrison SC. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282, 1669–1675 (1998).
   PubMed Web of Science ®Google Scholar
• ••First crystal structure of a ternary complexwith HIV-1 reverse transcriptase, DNA, and nucleoside triphosphate.
   Google Scholar
• Steitz TA. DNA polymerases: structural diversity and common mechanisms. J. Biol. Chem. 274, 17395–17398 (1999).
   PubMed Web of Science ®Google Scholar
• Spence RAWM, Anderson KS, Johnson KA, Kati. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 267, 988–993 (1995).
   PubMed Web of Science ®Google Scholar
• •First detailed kinetic study on non-nucleoside reverse transcriptase inhibitor (NNRTI) drug action.
   Google Scholar
• Rittinger K, Divita G, Goody RS. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by non-nucleoside inhibitors. Proc. Nad Acad. Sci. USA 92,8046–8049 (1995).
   PubMed Web of Science ®Google Scholar
• Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783–1790 (1992).
   PubMed Web of Science ®Google Scholar
• Krebs R, Immendorfer U, Thrall SH, Wohrl BM, Goody RS. Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. Biochemistry 36,10292–10300 (1997).
   PubMed Web of Science ®Google Scholar
• Anon D, Kaushik N, McCormick S, Borkow G, Parniak MA. 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. Biochemistry 37,15908–15917 (1998).
   PubMedGoogle Scholar
• Meyer PR, Matsuura SE, So AG, Scott WA. Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Proc. Nad Acad. Sci. USA 95, 13471–13476 (1998).
   PubMed Web of Science ®Google Scholar
• Isel C, Ehresmann C, Walter P, Ehresmann B, Marquet R. The emergence of different resistance mechanisms toward nucleoside inhibitors is explained by the properties of the wild-type HIV-1 reverse transcriptase. J. Biol. Chem. 276,48725–48732 (2001).
   PubMed Web of Science ®Google Scholar
• Gotte M, Anion D, Parniak MA, Wainberg MA. The Ml 84V mutation in the reverse transcriptase of human immunodeficiency virus Type 1 impairs rescue of chain-terminated DNA synthesis. J. Viral. 74, 3579–3585 (2000).
   PubMed Web of Science ®Google Scholar
• •First demonstration on diminished rates of excision associated with drug resistance conferring mutations.
   Google Scholar
• Quan Y, Brenner BG, Oliveira M, Wainberg MA. Lamivudine can exert a modest antiviral effect against human immunodeficiency virus Type 1 containing the Ml 84V mutation, Antimicrob. Agents Chemother. 47, 747–754 (2003).
   PubMed Web of Science ®Google Scholar
• Sarafianos SG, Das K, Clark AD Jr, et al. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with I3-branched amino acids. Proc. Nad Acad. Sci. USA 96, 10027–10032 (1999).
   PubMed Web of Science ®Google Scholar
• Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol. Cell. 4, 35–43 (1999).
   PubMed Web of Science ®Google Scholar
• ••First demonstration of the adenosinetriphosphate-dependent excision reaction as a possible mechanism for azidothymidine drug resistance.
   Google Scholar
• Ray AS, Murakami E, Basavapathruni A, et al. Probing the molecular mechanisms of AZT drug resistance mediated by HIV-1 reverse transcriptase using a transient kinetic analysis. Biochemistry 42,8831–8841 (2003).
   PubMed Web of Science ®Google Scholar
• Naeger LK, Margot NA, Miller MD. ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus Type 1 reverse transcriptase. Antimicrob. Agents Chemother. 46,2179–2184 (2002).
   PubMed Web of Science ®Google Scholar
• Girouard M, Diallo K, Marchand B, McCormick S, Gotte M. Mutations E44D and V118I in the reverse transcriptase of HIV-1 play distinct mechanistic roles in dual resistance to AZT and 3TC. J. Biol. Chem. 278, 34403–34410 (2003).
   PubMedGoogle Scholar
• Mas A, Parera M, Briones C, et al. Role of a dipeptide insertion between codons 69 and 70 of HIV-1 reverse transcriptase in the mechanism of AZT resistance. EMBO J. 19,5752–5761 (2000).
   PubMed Web of Science ®Google Scholar
• Deval J, Selmi B, Boretto J, et al. The molecular mechanism of multidrug resistance by the Q151M human immunodeficiency virus Type 1 reverse transcriptase and its suppression using a-boranophosphate nucleotide analogs. J. Biol. Chem. 277,42097–42104 (2002).
   PubMed Web of Science ®Google Scholar
• St Clair MH, Martin JL, Tudor-Williams G, et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 253, 1557–1559 (1991).
   PubMed Web of Science ®Google Scholar
• Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269, 696–699 (1995).
   PubMed Web of Science ®Google Scholar
• ••First demonstration of M184V-mediatedresensitization effects.
   Google Scholar
• Condra JH, Emini EA, Gotlib L, et al. Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob. Agents Chemother. 36,1441–1446 (1992).
   PubMed Web of Science ®Google Scholar
• Larder BA. 3'-azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus Type 1 resistance to nonnudeoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 36, 2664–2669 (1992).
   PubMed Web of Science ®Google Scholar
• Tachedjian G, Mellors J, Bazmi H, Birch C, Mills J. Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus Type 1 to foscarnet. J. Viral. 70, 7171–7181 (1996).
   PubMed Web of Science ®Google Scholar
• Wainberg MA, Miller MD, Quan Y, et al. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir. Ther. 4,87–94 (1999).
   PubMed Web of Science ®Google Scholar
• Wainberg MA, Drosopoulos WC, Salomon H, et al. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271,1282–1285 (1996).
   PubMed Web of Science ®Google Scholar
• Mansky LM, Le Rouzic E, Benichou S, Gajary LC. Influence of reverse transcriptase variants, drugs, and Vpr on human immunodeficiency virus Type 1 mutant frequencies. J. Viral. 77, 2071–2080 (2003).
   PubMedGoogle Scholar
• Back NK, Nijhuis M, Keulen W, et al. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J. 15, 4040–4049 (1996).
   PubMed Web of Science ®Google Scholar
• Diallo K, Marchand B, Wei X, Cellai L, Götte M, Wainberg MA. Diminished RNA primer usage associated with the L74V and Ml 84V mutations in the reverse transcriptase of human immunodeficiency virus Type 1 provides a possible mechanism for diminished viral replication capacity. J. Viral. 77,8621–8632 (2003).
   PubMed Web of Science ®Google Scholar
• Deval J, Navarro JM, Selmi B, et al. A loss of viral replicative capacity correlates with altered DNA polymerization kinetics by the human immunodeficiency virus reverse transcriptase bearing the K65R and L74V dideoxynucleoside resistance substitutions. J. Biol. Chem. 279, 25489–25496 (2004).
   PubMed Web of Science ®Google Scholar
• Ray AS, Basavapathruni A, Anderson KS. Mechanistic studies to understand the progressive development of resistance in human immunodeficiency virus Type 1 reverse transcriptase to abacavir. J. Biol. Chem. 277,40479–40490 (2002).
   PubMedGoogle Scholar
• Winston A, Mandalia S, Pillay D, Gazzard B, Pozniak A. The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients. AIDS 16,2087–2089 (2002).
   PubMed Web of Science ®Google Scholar
• Winston A, Pozniak A, Mandalia S, Gazzard B, Pillay D, Nelson M. Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase. AIDS 18, 949–951 (2004).
   PubMed Web of Science ®Google Scholar
• Roge BT, Katzenstein TL, Obel N, et al. K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine. Antivir. Then 8, 173–182 (2003).
   PubMed Web of Science ®Google Scholar
• Gu Z, Arts EJ, Parniak MA, Wainberg MA. Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus Type 1 shows diminished chain termination in the presence of 2',3'-dideoxycytidine 5'-triphosphate and other drugs. Proc. Nad Acad. Sci. USA 92, 2760–2764 (1995).
   PubMedGoogle Scholar
• Deval J, White KL, Miller MD, et al. Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations. J. Biol. Chem. 279, 509–516 (2004).
   PubMed Web of Science ®Google Scholar
• •Detailed kinetic analysis on the effects of K65R and M184V and implications for therapy.
   Google Scholar
• Parikh U, Koontz D, Hammond J, et al. K65R: a multinudeoside resistance mutation of low but increasing frequency. Antiviral Ther. 8, 152 (2003).
   Google Scholar
• Garcia-Lerma JG, MacInnes H, Bennett D, et al. A novel genetic pathway of human immunodeficiency virus Type 1 resistance to stavudine mediated by the K65R mutation. J. Viral. 77, 5685–5693 (2003).
   Google Scholar
• Das K, Ding J, Hsiou Y, et al. Crystal structures of 8-C1 and 9-C1 TIBO complexed with wild type HIV-1 RT and 8-C1 TIBO complexed with the TyR181Cys HIV-1 RT drug-resistant mutant. J. Mol. Biol. 264, 1085–1100 (1996).
   PubMed Web of Science ®Google Scholar
• Demeter LM, Shafer RW, Meehan PM, et al. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus Type 1 isolates from patients in a Phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrob. Agents Chemother. 44, 794–497 (2000).
   PubMedGoogle Scholar
• Wohrl BM, Krebs R, Thrall SH, Le Grice SF, Scheidig AJ, Goody RS. Kinetic analysis of four HIV-1 reverse transcriptase enzymes mutated in the primer grip region of p66. Implications for DNA synthesis and dimerization. J. Biol. Chem. 272, 17581–17587 (1997).
   PubMedGoogle Scholar
• Palaniappan C, Wisniewski M, Jacques PS, Le Grice SF, Fay PJ, Bambara RA. Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. J. Biol. Chem. 272, 11157–11164 (1997).
   PubMedGoogle Scholar
• Ghosh M, Jacques PS, Rodgers DW, Ottman M, Darlix JL, Le Grice SF. Alterations to the primer grip of p66 HIV-1 reverse transcriptase and their consequences for template-primer utilization. Biochemistry 35, 8553–8562 (1996).
   PubMedGoogle Scholar
• Powell MD, Ghosh M, Jacques PS, Howard KJ, Le Grice SF, Levin JG. Alanine-scanning mutations in the 'primer grip' of p66 HIV-1 reverse transcriptase result in selective loss of RNA priming activity. J. Biol. Chem. 272, 13262–13269 (1997).
   PubMedGoogle Scholar
• Ren J, Nichols C, Bird L, et al. Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors. J. Mol. Biol. 312, 795–805 (2001).
   PubMed Web of Science ®Google Scholar
• Spence RA, Anderson KS, Johnson KA. HIV-1 reverse transcriptase resistance to nonnucleoside inhibitors. Biochemistry 35, 1054–1063 (1996).
   PubMed Web of Science ®Google Scholar
• Hsiou Y, Ding J, Das K, et al. The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J. Mol. Biol. 309, 437–445 (2001).
   PubMed Web of Science ®Google Scholar
• •Demonstrates that limited access to the NNRTI binding site provides a possible mechanism for drug resistance.
   Google Scholar
• Maga G, Amacker M, Ruel N, Hubscher U, Spadari S. Resistance to nevirapine of HIV-1 reverse transcriptase mutants: loss of stabilizing interactions and thermodynamic or steric barriers are induced by different single amino acid substitutions. J. Mol. Biol. 274, 738–747 (1997).
   PubMed Web of Science ®Google Scholar
• Carr A, Vella S, de Jong MD, et al. A controlled trial of nevirapine plus zidovudine versus zidovudine alone in p24 antigenaemic HIV-infected patients. The Dutch—Italian—Australian Nevirapine Study Group. AIDS 10, 635–641 (1996).
   Google Scholar
• Richman D, Rosenthal AS, Skoog M, et al. BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus Type 1 and synergistic with zidovudine. Antimicrob. Agents Chemother. 35, 305–308 (1991).
   PubMed Web of Science ®Google Scholar
• Balzarini J, Pelemans H, Perez-Perez MJ, et al. Marked inhibitory activity of non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus Type 1 when combined with (-)2',3'-dideoxy-3'-thiacytidine. Mol. Pharmacol. 49, 882–890 (1996).
   PubMedGoogle Scholar
• Diallo K, Götte M, Wainberg MA. Molecular impact of the M184V mutation in human immunodeficiency virus Type 1 reverse transcriptase. Antimicrob. Agents Chemother. 47, 3377–3383 (2003).
   PubMed Web of Science ®Google Scholar
• Miller V, Stark T, Loeliger AE, Lange JM. The impact of the M184V substitution in HIV-1 reverse transcriptase on treatment response. HIV Med. 3, 135–145 (2002).
   PubMedGoogle Scholar
• Odriozola L, Cruchaga C, Andreola M, et al. Non-nucleoside inhibitors of HIV-1 reverse transcriptase inhibit phosphorolysis and resensitize the 3'-azido-3'-deoxythymidine (AZT)-resistant polymerase to AZT-5'-triphosphate. J. Biol. Chem. 278, 42710–42716 (2003).
   PubMedGoogle Scholar
• Borkow G, Anon D, Wainberg MA, Parniak MA. The thiocarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of 3'-azido-3'-deoxythymidine (AZT) against AZT-resistant human immunodeficiency virus Type 1. Antimicrob. Agents Chemother. 43, 259–263 (1999).
   PubMedGoogle Scholar
• Basavapathruni A, Bailey CM, Anderson KS. Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs. J. Biol. Chem. 279, 6221–6224 (2004).
   PubMedGoogle Scholar
• Rodgers DW, Gamblin SJ, Harris BA, et al. The structure of unliganded reverse transcriptase from the human immunodeficiency virus Type 1. Proc. Nad Acad. Sci. USA 92,1222–1226 (1995).
   PubMed Web of Science ®Google Scholar
• Stammers DK, Somers DO, Ross CK, et al. Crystals of HIV-1 reverse transcriptase diffracting to 2.2 A resolution. J. Mal. Biol. 242, 586–588 (1994).
   PubMedGoogle Scholar
• Whitcomb JM, Huang W Limoli K, et al . Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates. AIDS 16, F41—F47 (2002).
   Web of Science ®Google Scholar
• Haubrich RH, Kemper CA, Hellmann NS, et al. The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis. AIDS 16, F33—F40 (2002).
   PubMed Web of Science ®Google Scholar
• Shulman N, Zolopa AR, Passaro D, et al. Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy. AIDS 15, 1125–1132(2001).
   PubMed Web of Science ®Google Scholar
• •First demonstration of NNRTI hypersusceptibility.
   Google Scholar
• Crumpacker CS. Mechanism of action of foscarnet against viral polymerases. Am. J. Med. 92, S3—S7 (1992).
   Google Scholar
• Shaw-Reid CA, Munshi V, Graham P, et al. Inhibition of HIV-1 ribonuclease H by a novel diketo acid, 445-(benzoylamino)thien-2-yll-2,4-dioxobutanoic acid. J. Biol. Chem. 278, 2777–2780 (2003).
   PubMed Web of Science ®Google Scholar
• •Development of specific ribonuclease (RNase) H inhibitors.
   Google Scholar
• Anon D, Sluis-Cremer N, Parniak MA. Mechanism by which phosphonoformic acid resistance mutations restore 3'-azido-3'-deoxythymidine (AZT) sensitivity to AZT-resistant HIV-1 reverse transcriptase. J. Biol. Chem. 275, 9251–9255 (2000).
   PubMedGoogle Scholar
• Meyer PR, Matsuura SE, Zonarich D, et al. Relationship between 3'-azido-3'-deoxythymidine resistance and primer unblocking activity in foscarnet-resistant mutants of human immunodeficiency virus Type 1 reverse transcriptase. J. Viral. 77, 6127–6137 (2003).
   PubMed Web of Science ®Google Scholar
• Hammond JL, Koontz DL, Bazmi HZ, et al. Alkylglycerol prodrugs of phosphonoformate are potent in vitro inhibitors of nucleoside-resistant human immunodeficiency virus Type 1 and select for resistance mutations that suppress zidovudine resistance. Antimicrob. Agents Chemother. 45, 1621–1628 (2001).
   PubMed Web of Science ®Google Scholar
• •Characterization of novel prodrugs of foscarnet.
   Google Scholar
• Parniak MA, McBurney S, Oldfield E, Mellors JW. Bisphosphonate inhibitors of nucleosid reverse transcriptase inhibitor excision. Antiviral The,: 9, 32 (2004).
   Google Scholar
• Davis WR, Tomsho J, Nikam S, Cook EM, Somand D, Peliska JA. Inhibition of HIV-1 reverse transcriptase-catalyzed DNA strand transfer reactions by 4-chlorophenylhydrazone of mesoxalic acid. Biochemistry 39, 14279–14291 (2000).
   PubMed Web of Science ®Google Scholar
• Borkow G, Fletcher RS, Barnard J, et al. Inhibition of the ribonuclease H and DNA polymerase activities of HIV-1 reverse transcriptase by N-(4-tert-butylbenzoy1)-2-hydroxy-1-naphthaldehyde hydrazone. Biochemistry 36, 3179–3185 (1997).
   PubMed Web of Science ®Google Scholar
• Gabbara S, Davis WR, Hupe L, Hupe D, Peliska JA. Inhibitors of DNA strand transfer reactions catalyzed by HIV-1 reverse transcriptase. Biochemistry 38, 13070–13076 (1999).
   PubMed Web of Science ®Google Scholar
• Klumpp K, Hang JQ, Rajendran S, et al. Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors. Nucleic Acids Res. 31, 6852–6859 (2003).
   PubMed Web of Science ®Google Scholar
• •Development of specific RNase H inhibitors.
   Google Scholar
• Sluis-Cremer N, Anion D, Parniak MA. Destabilization of the HIV-1 reverse transcriptase dimer upon interaction with N-acyl hydrazone inhibitors. Mol. Pharmacol. 62, 398–405 (2002).
   PubMedGoogle Scholar
• Morris MC, Robert-Hebmann V, Chaloin L, et al. A new potent HIV-1 reverse transcriptase inhibitor. A synthetic peptide derived from the interface subunit domains. J. Biol. Chem. 274, 24941–24946 (1999).
   PubMedGoogle Scholar
• Palaniappan C, Fay PJ, Bambara RA. Nevirapine alters the cleavage specificity of ribonuclease H of human immunodeficiency virus 1 reverse transcriptase. J. Biol. Chem. 270, 4861–4869 (1995).
   PubMed Web of Science ®Google Scholar
• Tachedjian G, Orlova M, Sarafianos SG, Arnold E, Goff SR Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV Type 1 reverse transcriptase. Proc. Natl Acad. Sci. USA 98, 7188–7193 (2001).
   PubMed Web of Science ®Google Scholar
• d'Abramo CM, Cellai L, Götte M. Excision of incorporated nucleotide analog chain terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases. J. Mol. Biol. 337, 1–14 (2004).
   PubMedGoogle Scholar