Overcoming HIV drug resistance through rational drug design based on molecular, biochemical, and structural profiles of HIV resistance

Abstract.There are 20 available drugs for the treatment of human immunodeficiency virus (HIV) infection. With a single exception, all of these drugs inhibit either HIV reverse transcriptase or protease. Reverse transcriptase inhibitors can be further categorized as nucleoside/nucleotide analogs or non-nucleoside reverse transcriptase inhibitors. Resistance that has emerged against all available antiretroviral drugs represents a major challenge in the therapy of HIV infection. Nevertheless, extensive analysis of the molecular and structural mechanisms by which such mutations confer resistance has accumulated over the years. This understanding has driven the development and refinement of novel compounds capable of maintaining antiviral activity against both wild-type and drug-resistant HIV strains. The molecular, biochemical, and structural profiles of reverse transcriptase inhibitor and protease inhibitor resistance are discussed. In addition, how this knowledge has been utilized to generate a new generation of antiviral drugs with activity against drug-resistant HIV is reviewed.

[1]  D. Walters,et al.  Structure based design: novel spirocyclic ethers as nonpeptidal P2-ligands for HIV protease inhibitors. , 1998, Bioorganic & medicinal chemistry letters.

[2]  H. Mitsuya,et al.  Enzymatic Characterization of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistant to Multiple 2′,3′-Dideoxynucleoside 5′-Triphosphates (*) , 1995, The Journal of Biological Chemistry.

[3]  Ladislau C. Kovari,et al.  Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity , 2004, Journal of Virology.

[4]  Victor DeGruttola,et al.  Clinically Validated Genotype Analysis: Guiding Principles and Statistical Concerns , 2004, Antiviral therapy.

[5]  J. Erickson,et al.  Impact of Human Immunodeficiency Virus Type 1 gp41 Amino Acid Substitutions Selected during Enfuvirtide Treatment on gp41 Binding and Antiviral Potency of Enfuvirtide In Vitro , 2005, Journal of Virology.

[6]  M. A. McClure,et al.  Computer analysis of retroviral pol genes: assignment of enzymatic functions to specific sequences and homologies with nonviral enzymes. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Kappes,et al.  Emergence of Resistant Human Immunodeficiency Virus Type 1 in Patients Receiving Fusion Inhibitor (T-20) Monotherapy , 2002, Antimicrobial Agents and Chemotherapy.

[8]  Michael Ames,et al.  A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy , 2002, AIDS.

[9]  P. Boyer,et al.  Fixed conformation nucleoside analogs effectively inhibit excision-proficient HIV-1 reverse transcriptases. , 2005, Journal of molecular biology.

[10]  E. Freire,et al.  Adaptive inhibitors of the HIV-1 protease. , 2005, Progress in biophysics and molecular biology.

[11]  D. Hazuda,et al.  HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications. , 2004, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[12]  Celia A Schiffer,et al.  Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. , 2005, Journal of medicinal chemistry.

[13]  N. Sluis-Cremer,et al.  Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs) , 2000, Cellular and Molecular Life Sciences CMLS.

[14]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 1: From alpha-anilinophenylacetamide (alpha-APA) to imidoyl thiourea (ITU). , 2001, Bioorganic & medicinal chemistry letters.

[15]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 1: From α-Anilinophenylacetamide (α-APA) to imidoyl thiourea (ITU) , 2001 .

[16]  Celia A Schiffer,et al.  Combating susceptibility to drug resistance: lessons from HIV-1 protease. , 2004, Chemistry & biology.

[17]  T. Steitz,et al.  Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. , 1992, Science.

[18]  D. Lamarre,et al.  Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors , 1996, Journal of virology.

[19]  T. Steitz,et al.  Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Hsinyi Tsang,et al.  Amino Acid Substitutions in Gag Protein at Non-cleavage Sites Are Indispensable for the Development of a High Multitude of HIV-1 Resistance against Protease Inhibitors* , 2002, The Journal of Biological Chemistry.

[21]  Arun K. Ghosh,et al.  A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site , 2002, Journal of Virology.

[22]  C. Schiffer,et al.  How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease. , 2000, Journal of molecular biology.

[23]  John H Elder,et al.  Is resistance futile? , 2003, Current drug targets. Infectious disorders.

[24]  H. M. Vinkers,et al.  Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. , 2004, Journal of medicinal chemistry.

[25]  Amalio Telenti,et al.  Update of the Drug Resistance Mutations in HIV-1: 2005. , 2005, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[26]  D. Katzenstein,et al.  Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. , 1994, The Journal of infectious diseases.

[27]  R. Grant,et al.  Activity of a ritonavir plus saquinavir‐containing regimen in patients with virologic evidence of indinavir or ritonavir failure , 1998, AIDS.

[28]  M. Matsuoka,et al.  4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro , 2001, Antimicrobial Agents and Chemotherapy.

[29]  A. D. Clark,et al.  Structures of HIV‐1 reverse transcriptase with pre‐ and post‐translocation AZTMP‐terminated DNA , 2002, The EMBO journal.

[30]  Cassandra B. Jabara,et al.  Enfuvirtide Resistance Mutations: Impact on Human Immunodeficiency Virus Envelope Function, Entry Inhibitor Sensitivity, and Virus Neutralization , 2005, Journal of Virology.

[31]  G L Verdine,et al.  Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. , 1998, Science.

[32]  M. Parniak,et al.  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. , 1998, Biochemistry.

[33]  M. Hattori,et al.  Inhibitory effects of quinones on RNase H activity associated with HIV‐1 reverse transcriptase , 2002, Phytotherapy research : PTR.

[34]  K D Watenpaugh,et al.  Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. , 1998, Journal of medicinal chemistry.

[35]  D. Ho,et al.  Ordered accumulation of mutations in HIV protease confers resistance to ritonavir , 1996, Nature Medicine.

[36]  J. Condra,et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors , 1995, Nature.

[37]  L J Davis,et al.  Active human immunodeficiency virus protease is required for viral infectivity. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Lin Hong,et al.  Active‐site mobility in human immunodeficiency virus, type 1, protease as demonstrated by crystal structure of A28S mutant , 1998, Protein science : a publication of the Protein Society.

[39]  Lidia Ruiz,et al.  Clinical utility of HIV-1 genotyping and expert advice: the Havana trial , 2002, AIDS.

[40]  B. Anderson,et al.  Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Condra,et al.  Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors , 1993, Antimicrobial Agents and Chemotherapy.

[42]  S. Sarafianos,et al.  Nucleoside Analog Resistance Caused by Insertions in the Fingers of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involves ATP-Mediated Excision , 2002, Journal of Virology.

[43]  J. Schapiro,et al.  Drug-resistance genotyping in HIV-1 therapy: the VIRAD APT randomi sed controlled trial , 1999, The Lancet.

[44]  J. Mellors,et al.  The 3′-Azido Group Is Not the Primary Determinant of 3′-Azido-3′-deoxythymidine (AZT) Responsible for the Excision Phenotype of AZT-resistant HIV-1* , 2005, Journal of Biological Chemistry.

[45]  Henri Moereels,et al.  Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors , 1995, Nature Structural Biology.

[46]  C. Boucher,et al.  In-vitro tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors. , 2000, AIDS.

[47]  E D Blair,et al.  Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors , 1995, Antimicrobial agents and chemotherapy.

[48]  D. Richman,et al.  HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. , 1989, Science.

[49]  S. Sarafianos,et al.  Designing anti-AIDS drugs targeting the major mechanism of HIV-1 RT resistance to nucleoside analog drugs. , 2004, The international journal of biochemistry & cell biology.

[50]  A. D. Clark,et al.  The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. , 2001, Journal of molecular biology.

[51]  R. S. Goody,et al.  Multiparameter single-molecule fluorescence spectroscopy reveals heterogeneity of HIV-1 reverse transcriptase:primer/template complexes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  E. Arnold,et al.  Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[53]  D. Schake.  How flexible is tipranavir in complex with the HIV-1 protease active site? , 2004, AIDS.

[54]  C. Schiffer,et al.  Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy , 2003, Journal of Virology.

[55]  J. Hsieh,et al.  Kinetic mechanism of the DNA-dependent DNA polymerase activity of human immunodeficiency virus reverse transcriptase. , 1993, The Journal of biological chemistry.

[56]  K. Chou,et al.  Predicting human immunodeficiency virus protease cleavage sites in proteins by a discriminant function method , 1996, Proteins.

[57]  Irene T Weber,et al.  High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. , 2004, Journal of molecular biology.

[58]  T. Dahl,et al.  Capravirine, a nonnucleoside reverse-transcriptase inhibitor in patients infected with HIV-1: a phase 1 study. , 2004, The Journal of infectious diseases.

[59]  S. Sarafianos,et al.  Mutation of Amino Acids in the Connection Domain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase That Contact the Template-Primer Affects RNase H Activity , 2003, Journal of Virology.

[60]  Hiroshi Harada,et al.  S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1 , 1998, Antimicrobial Agents and Chemotherapy.

[61]  R. Esnouf,et al.  Mutational analysis of trp-229 of human immunodeficiency virus type 1 reverse transcriptase (RT) identifies this amino acid residue as a prime target for the rational design of new non-nucleoside RT inhibitors. , 2000, Molecular pharmacology.

[62]  A. D. Clark,et al.  Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Falloon,et al.  Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites , 1997, Journal of virology.

[64]  D. Stuart,et al.  A Family of Insertion Mutations between Codons 67 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Multinucleoside Analog Resistance , 1999, Antimicrobial Agents and Chemotherapy.

[65]  A. So,et al.  Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[66]  S D Kemp,et al.  Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. , 1991, Science.

[67]  R. Laufs,et al.  Primary genotypic resistance of HIV-1 to the fusion inhibitor T-20 in long-term infected patients. , 2001, AIDS.

[68]  L. Bourgon,et al.  Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. , 2005, Antiviral research.

[69]  B. J. Betts,et al.  High Degree of Interlaboratory Reproducibility of Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Sequencing of Plasma Samples from Heavily Treated Patients , 2001, Journal of Clinical Microbiology.

[70]  K A Johnson,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors , 1995, Science.

[71]  Tomozumi Imamichi,et al.  Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors. , 2004, Current pharmaceutical design.

[72]  S. Pettit,et al.  The regulation of sequential processing of HIV-1 Gag by the viral protease. , 1998, Advances in experimental medicine and biology.

[73]  V. Pathak,et al.  Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: balance between RNase H activity and nucleotide excision. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[74]  K. Anderson,et al.  Mechanism and fidelity of HIV reverse transcriptase. , 1992, The Journal of biological chemistry.

[75]  Arun K. Ghosh,et al.  Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors. , 2005, Journal of medicinal chemistry.

[76]  Brendan A. Larder,et al.  Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples , 2000, AIDS.

[77]  S. Sarafianos,et al.  Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. , 2004, Current opinion in structural biology.

[78]  T. Kunkel,et al.  Biochemical studies on the reverse transcriptase and RNase H activities from human immunodeficiency virus strains resistant to 3'-azido-3'-deoxythymidine. , 1992, The Journal of biological chemistry.

[79]  D. Decamp,et al.  Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease ( HIV‐PR): Design, Enzyme Binding and Selectivity, Antiviral Efficacy, and Cell Permeability Properties. , 1995 .

[80]  Yvonne Jones,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors , 1995, Nature Structural Biology.

[81]  H. Mitsuya,et al.  Potential of 4′-C-Substituted Nucleosides for the Treatment of HIV-1 , 2004, Antiviral chemistry & chemotherapy.

[82]  D. Venzon,et al.  Altered drug sensitivity, fitness, and evolution of human immunodeficiency virus type 1 with pol gene mutations conferring multi-dideoxynucleoside resistance. , 1998, The Journal of infectious diseases.

[83]  M. Moroni,et al.  Susceptibility to PNU-140690 (Tipranavir) of Human Immunodeficiency Virus Type 1 Isolates Derived from Patients with Multidrug Resistance to Other Protease Inhibitors , 2000, Antimicrobial Agents and Chemotherapy.

[84]  D. Walters,et al.  Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation. , 1996, Journal of medicinal chemistry.

[85]  S. Sarafianos,et al.  Effects of the Δ67 Complex of Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Nucleoside Analog Excision , 2004, Journal of Virology.

[86]  E. De Clercq.  Antiviral drug discovery and development: where chemistry meets with biomedicine. , 2005, Antiviral research.

[87]  Sek Mardy,et al.  Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors , 2004, Journal of Virology.

[88]  D. Hazuda,et al.  Inhibition of HIV-1 Ribonuclease H by a Novel Diketo Acid, 4-[5-(Benzoylamino)thien-2-yl]-2,4-dioxobutanoic Acid* , 2003, The Journal of Biological Chemistry.

[89]  A. Gronenborn,et al.  HIV-I protease: Maturation, enzyme specificity, and drug resistance , 2000 .

[90]  Brendan A. Larder,et al.  Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples , 2000, AIDS.

[91]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues. , 2001, Bioorganic & medicinal chemistry letters.

[92]  H. Ohrui,et al.  Synthesis of the L-Enantiomer of 4'-C-Ethynyl-2'-deoxycytidine , 2001, Bioscience, biotechnology, and biochemistry.

[93]  Pierre-Marie Girard,et al.  Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial , 2002, AIDS.

[94]  R. Haubrich,et al.  A randomized, prospective study of phenotype susceptibility testing versus standard of care to manage antiretroviral therapy: CCTG 575 , 2005, AIDS.

[95]  P. Boyer,et al.  Resistance to 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives is generated by mutations at multiple sites in the HIV-1 reverse transcriptase. , 1995, Virology.

[96]  S. Sarafianos,et al.  Mutations in the RNase H domain of HIV-1 reverse transcriptase affect the initiation of DNA synthesis and the specificity of RNase H cleavage in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[97]  J. Sninsky,et al.  Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). , 1995, The Journal of infectious diseases.

[98]  A. Gronenborn,et al.  HIV-1 protease: maturation, enzyme specificity, and drug resistance. , 2000, Advances in pharmacology.

[99]  R F Schinazi,et al.  Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides , 1993, Antimicrobial Agents and Chemotherapy.

[100]  Celia A. Schiffer,et al.  Structural and Thermodynamic Basis for the Binding of TMC114, a Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor , 2004, Journal of Virology.

[101]  C. Schiffer,et al.  Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes. , 2002, Structure.

[102]  E. Clercq,et al.  Antiviral drug discovery and development: where chemistry meets with biomedicine. , 2005, Antiviral research.

[103]  E. De Clercq,et al.  The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. , 1998, Antiviral research.

[104]  D W Barry,et al.  3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[105]  R. Haubrich,et al.  Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors , 2001, AIDS.

[106]  D. Hazuda,et al.  Dissecting the effects of DNA polymerase and ribonuclease H inhibitor combinations on HIV-1 reverse-transcriptase activities. , 2005, Biochemistry.

[107]  Wolfgang Resch,et al.  Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors , 2003, Antimicrobial Agents and Chemotherapy.

[108]  D. Ho,et al.  Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor , 1997, Antimicrobial agents and chemotherapy.

[109]  Stephen H Hughes,et al.  Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. , 2005, Progress in biophysics and molecular biology.

[110]  Jianping Ding,et al.  Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. , 1994, Journal of molecular biology.

[111]  C. Tarby.  Recent advances in the development of next generation non-nucleoside reverse transcriptase inhibitors. , 2004, Current topics in medicinal chemistry.

[112]  T. Merigan,et al.  Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years , 1997, Antimicrobial agents and chemotherapy.

[113]  Keisuke Yusa,et al.  Acquisition of multi-PI (protease inhibitor) resistance in HIV-1 in vivo and in vitro. , 2004, Current pharmaceutical design.

[114]  Celia A Schiffer,et al.  Design of HIV-1 protease inhibitors active on multidrug-resistant virus. , 2005, Journal of medicinal chemistry.

[115]  Erik De Clercq,et al.  The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection , 1998 .

[116]  A. D. Clark,et al.  Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[117]  R. Schooley,et al.  Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF , 2002, AIDS.

[118]  Stephen H Hughes,et al.  In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). , 2005, Journal of medicinal chemistry.

[119]  S. Sarafianos,et al.  Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase , 2001, Journal of Virology.

[120]  B. Larder,et al.  Effects of Dipeptide Insertions between Codons 69 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Primer Unblocking, Deoxynucleoside Triphosphate Inhibition, and DNA Chain Elongation , 2003, Journal of Virology.

[121]  Miguel Ángel Martínez,et al.  Role of a dipeptide insertion between codons 69 and 70 of HIV‐1 reverse transcriptase in the mechanism of AZT resistance , 2000, The EMBO journal.

[122]  P. Boyer,et al.  Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[123]  Christos J. Petropoulos,et al.  A Novel Phenotypic Drug Susceptibility Assay for Human Immunodeficiency Virus Type 1 , 2000, Antimicrobial Agents and Chemotherapy.

[124]  Michael D Miller,et al.  K65R, TAMs and tenofovir. , 2004, AIDS reviews.

[125]  Dirk Jochmans,et al.  TMC114, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor Active against Protease Inhibitor-Resistant Viruses, Including a Broad Range of Clinical Isolates , 2005, Antimicrobial Agents and Chemotherapy.

[126]  Klarmann Gj,et al.  Uncovering the complexities of retroviral ribonuclease H reveals its potential as a therapeutic target. , 2002 .

[127]  Arun K. Ghosh,et al.  Altered HIV-1 Gag Protein Interactions with Cyclophilin A (CypA) on the Acquisition of H219Q and H219P Substitutions in the CypA Binding Loop* , 2006, Journal of Biological Chemistry.

[128]  P. Anderson,et al.  Structure-based design of HIV-1 protease inhibitors: replacement of two amides and a 10 pi-aromatic system by a fused bis-tetrahydrofuran. , 1994, Journal of medicinal chemistry.