hiv integrase

Summary

Summary: Enzyme of the HUMAN IMMUNODEFICIENCY VIRUS that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene.

Top Publications

  1. Tang J, Maddali K, Metifiot M, Sham Y, Vince R, Pommier Y, et al. 3-Hydroxypyrimidine-2,4-diones as an inhibitor scaffold of HIV integrase. J Med Chem. 2011;54:2282-92 pubmed publisher
    ..These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold. ..
  2. Tsuruyama T, Nakai T, Hiratsuka T, Jin G, Nakamura T, Yoshikawa K. In vitro HIV-1 selective integration into the target sequence and decoy-effect of the modified sequence. PLoS ONE. 2010;5:e13841 pubmed publisher
  3. De Luca L, Gitto R, Christ F, Ferro S, De Grazia S, Morreale F, et al. 4-[1-(4-Fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process. Antiviral Res. 2011;92:102-7 pubmed publisher
    ..This work has suggested the possibility of also constructing an integration dual inhibitor using a design-in strategy. ..
  4. Johnson B, Metifiot M, Pommier Y, Hughes S. Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity. Antimicrob Agents Chemother. 2012;56:411-9 pubmed publisher
  5. Li Z, Wu S, Wang J, Li W, Lin Y, Ji C, et al. Evaluation of the interactions of HIV-1 integrase with small ubiquitin-like modifiers and their conjugation enzyme Ubc9. Int J Mol Med. 2012;30:1053-60 pubmed publisher
    ..These findings merit further investigation because of their potentially significant implications for the cellular antiviral response to HIV-1 infection. ..
  6. Mouscadet J, Delelis O, Marcelin A, Tchertanov L. Resistance to HIV-1 integrase inhibitors: A structural perspective. Drug Resist Updat. 2010;13:139-50 pubmed publisher
    ..of which raltegravir, elvitegravir and S/GSK1349572, is a new class of antiretrovirals that inhibit HIV integrase-catalyzed insertion of the HIV-1 genome into cell chromosomes...
  7. Kessl J, Li M, Ignatov M, Shkriabai N, Eidahl J, Feng L, et al. FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75. Nucleic Acids Res. 2011;39:9009-22 pubmed publisher
  8. Turriziani O, Montagna C, Falasca F, Bucci M, Russo G, Lichtner M, et al. Short communication: analysis of the integrase gene from HIV type 1-positive patients living in a rural area of West Cameroon. AIDS Res Hum Retroviruses. 2012;28:1729-33 pubmed publisher
  9. Kawasuji T, Johns B, Yoshida H, Weatherhead J, Akiyama T, Taishi T, et al. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J Med Chem. 2013;56:1124-35 pubmed publisher
    ..The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation. ..

More Information

Publications104 found, 100 shown here

  1. Canducci F, Marinozzi M, Sampaolo M, Boeri E, Spagnuolo V, Gianotti N, et al. Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir. J Antimicrob Chemother. 2010;65:425-33 pubmed publisher
    ..These results may have implications either for the evaluation of genotypic results, or for the correct clinical use of the compound. ..
  2. Ceccherini Silberstein F, Van Baelen K, Armenia D, Trignetti M, Rondelez E, Fabeni L, et al. Secondary integrase resistance mutations found in HIV-1 minority quasispecies in integrase therapy-naive patients have little or no effect on susceptibility to integrase inhibitors. Antimicrob Agents Chemother. 2010;54:3938-48 pubmed publisher
  3. Billamboz M, Bailly F, Lion C, Calmels C, Andreola M, Witvrouw M, et al. 2-hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4. Eur J Med Chem. 2011;46:535-46 pubmed publisher
    ..However these identified integrase inhibitors provide a very good basis for the development of new hits. ..
  4. Geretti A, Armenia D, Ceccherini Silberstein F. Emerging patterns and implications of HIV-1 integrase inhibitor resistance. Curr Opin Infect Dis. 2012;25:677-86 pubmed publisher
    ..Prompt management of RAL and EVG failure is required to prevent the accumulation of multiple resistance mutations that reduce DTG susceptibility. ..
  5. Hobaika Z, Zargarian L, Maroun R, Mauffret O, Burke T, Fermandjian S. HIV-1 integrase and virus and cell DNAs: complex formation and perturbation by inhibitors of integration. Neurochem Res. 2010;35:888-93 pubmed publisher
    ..This explains why TB11 is an inhibitor of strand transfer but not of 3'-processing. These results can help in the search of new IN inhibitors. ..
  6. Da Silva D, Van Wesenbeeck L, Breilh D, Reigadas S, Anies G, Van Baelen K, et al. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother. 2010;65:1262-9 pubmed publisher
    ..Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution. ..
  7. Nouhin J, Donchai T, Hoang K, Ken S, Kamkorn J, Tran T, et al. Natural polymorphisms of HIV-1 CRF01_AE integrase coding region in ARV-naïve individuals in Cambodia, Thailand and Vietnam: an ANRS AC12 working group study. Infect Genet Evol. 2011;11:38-43 pubmed publisher
    The HIV integrase enzyme is essential for the HIV life cycle as it mediates integration of HIV-1 proviral DNA into the infected cell's genome...
  8. Zamborlini A, Coiffic A, Beauclair G, Delelis O, Paris J, Koh Y, et al. Impairment of human immunodeficiency virus type-1 integrase SUMOylation correlates with an early replication defect. J Biol Chem. 2011;286:21013-22 pubmed publisher
    ..Because SUMOylation-defective IN mutants retained WT catalytic activity, we hypothesize that SUMOylation might regulate the affinity of IN for co-factors, contributing to efficient HIV-1 replication. ..
  9. Tintori C, Demeulemeester J, Franchi L, Massa S, Debyser Z, Christ F, et al. Discovery of small molecule HIV-1 integrase dimerization inhibitors. Bioorg Med Chem Lett. 2012;22:3109-14 pubmed publisher
  10. Fransen S, Gupta S, Frantzell A, Petropoulos C, Huang W. Substitutions at amino acid positions 143, 148, and 155 of HIV-1 integrase define distinct genetic barriers to raltegravir resistance in vivo. J Virol. 2012;86:7249-55 pubmed publisher
    ..These selective pressures result in the displacement of N155H variants by 143 or 148 variants under continued drug exposure. ..
  11. Tsiang M, Jones G, Hung M, Mukund S, Han B, Liu X, et al. Affinities between the binding partners of the HIV-1 integrase dimer-lens epithelium-derived growth factor (IN dimer-LEDGF) complex. J Biol Chem. 2009;284:33580-99 pubmed publisher
    ..This study revealed the significantly tighter nature of the IN-IN dimer compared with the IN-LEDGF interaction. ..
  12. Singh N, Ranjan A, Sur S, Chandra R, Tandon V. Inhibition of HIV-1 Integrase gene expression by 10-23 DNAzyme. J Biosci. 2012;37:493-502 pubmed
    b>HIV Integrase (IN) is an enzyme that is responsible for the integration of the proviral genome into the human genome, and this integration step is the first step of the virus hijacking the human cell machinery for its propagation and ..
  13. Sorin M, Cano J, Das S, Mathew S, Wu X, Davies K, et al. Recruitment of a SAP18-HDAC1 complex into HIV-1 virions and its requirement for viral replication. PLoS Pathog. 2009;5:e1000463 pubmed publisher
    ..Furthermore, HIV-1 virion-associated HDAC1 is required for efficient early post-entry events, indicating a novel role for HDAC1 during HIV-1 replication. ..
  14. Bar Magen T, Donahue D, McDonough E, Kuhl B, Faltenbacher V, Xu H, et al. HIV-1 subtype B and C integrase enzymes exhibit differential patterns of resistance to integrase inhibitors in biochemical assays. AIDS. 2010;24:2171-9 pubmed publisher
    ..It is possible that different viral subtypes may favor different mutational pathways, potentially leading to varying levels of drug resistance among different subtypes. ..
  15. Zhao X, Maddali K, Smith S, Métifiot M, Johnson B, Marchand C, et al. 6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors. Bioorg Med Chem Lett. 2012;22:7309-13 pubmed publisher
  16. Sippel M, Sotriffer C. Molecular dynamics simulations of the HIV-1 integrase dimerization interface: guidelines for the design of a novel class of integrase inhibitors. J Chem Inf Model. 2010;50:604-14 pubmed publisher
    ..Both were shown to be suited for accommodating an inhibitory peptide. The results form a valuable basis for the design of ligands targeting the dimerization interface and, thus, of a whole new class of HIV-1 integrase inhibitors. ..
  17. Mukundan V, Do N, Phan A. HIV-1 integrase inhibitor T30177 forms a stacked dimeric G-quadruplex structure containing bulges. Nucleic Acids Res. 2011;39:8984-91 pubmed publisher
    ..In this work, we also propose a simple analytical approach to stoichiometry determination using concentration-dependent melting curves. ..
  18. Garrido C, Geretti A, Zahonero N, Booth C, Strang A, Soriano V, et al. Integrase variability and susceptibility to HIV integrase inhibitors: impact of subtypes, antiretroviral experience and duration of HIV infection. J Antimicrob Chemother. 2010;65:320-6 pubmed publisher
    Little is known about the extent and predictors of polymorphisms potentially influencing the susceptibility to HIV integrase inhibitors (INIs)...
  19. Ceccherini Silberstein F, Malet I, Fabeni L, Dimonte S, Svicher V, D Arrigo R, et al. Specific HIV-1 integrase polymorphisms change their prevalence in untreated versus antiretroviral-treated HIV-1-infected patients, all naive to integrase inhibitors. J Antimicrob Chemother. 2010;65:2305-18 pubmed publisher
    ..The potential contribution of such polymorphisms to the evolution of resistance under the pressure of INIs needs further investigation. ..
  20. Hare S, Di Nunzio F, Labeja A, Wang J, Engelman A, Cherepanov P. Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathog. 2009;5:e1000515 pubmed publisher
    ..Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor...
  21. Kantor B, Ma H, Webster Cyriaque J, Monahan P, Kafri T. Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection. Proc Natl Acad Sci U S A. 2009;106:18786-91 pubmed publisher
    ..Finally, we propose a mechanism describing the role of episomal HIV-1 forms in the viral life cycle in a SCFA-rich gut environment. ..
  22. Ao Z, Jayappa K, Wang B, Zheng Y, Wang X, Peng J, et al. Contribution of host nucleoporin 62 in HIV-1 integrase chromatin association and viral DNA integration. J Biol Chem. 2012;287:10544-55 pubmed publisher
    ..Taken together, these results indicate that the cellular Nup62 is specifically recruited by HIV-1 IN and contribute to an efficient viral DNA integration. ..
  23. Charpentier C, Laureillard D, Piketty C, Tisserand P, Batisse D, Karmochkine M, et al. High frequency of integrase Q148R minority variants in HIV-infected patients naive of integrase inhibitors. AIDS. 2010;24:867-73 pubmed publisher
    ..Although their presence was not consistently associated with virological failure, their impact on long-term viral suppression needs to be further investigated. ..
  24. Watanabe T, Murakoshi H, Gatanaga H, Koyanagi M, Oka S, Takiguchi M. Effective recognition of HIV-1-infected cells by HIV-1 integrase-specific HLA-B?4002-restricted T cells. Microbes Infect. 2011;13:160-6 pubmed publisher
    ..These integrase-specific T cells with high antigen sensitivity may contribute to the suppression of HIV-1 replication in HIV-1-infected HLA-B?4002+ individuals. ..
  25. Malet I, Wirden M, Fourati S, Armenia D, Masquelier B, Fabeni L, et al. Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients. J Antimicrob Chemother. 2011;66:1481-3 pubmed publisher
    ..The impact of raltegravir-mediated changes such as these on the virological response to S/GSK1349572 should be studied further. ..
  26. Wielens J, Headey S, Jeevarajah D, Rhodes D, Deadman J, Chalmers D, et al. Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site. FEBS Lett. 2010;584:1455-62 pubmed publisher
    b>HIV integrase (IN) is an essential enzyme in HIV replication and an important target for drug design. IN has been shown to interact with a number of cellular and viral proteins during the integration process...
  27. De Luca L, Ferro S, Morreale F, De Grazia S, Chimirri A. Inhibitors of the interactions between HIV-1 IN and the cofactor LEDGF/p75. ChemMedChem. 2011;6:1184-91 pubmed publisher
    ..We describe herein the progress to date in developing inhibitors of this promising target. ..
  28. Feng L, Sharma A, Slaughter A, Jena N, Koh Y, Shkriabai N, et al. The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem. 2013;288:15813-20 pubmed publisher
    ..Our findings provide the structural foundations for developing improved ALLINIs with increased potency and decreased potential to select for drug resistance. ..
  29. Di Fenza A, Rocchia W, Tozzini V. Complexes of HIV-1 integrase with HAT proteins: multiscale models, dynamics, and hypotheses on allosteric sites of inhibition. Proteins. 2009;76:946-58 pubmed publisher
    ..Taken together these findings suggest a way to affect the acetyltransferase binding by an allosteric type of inhibition and provide an important new approach for the drug design against HIV disease. ..
  30. Zhao X, Maddali K, Vu B, Marchand C, Hughes S, Pommier Y, et al. Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. Bioorg Med Chem Lett. 2009;19:2714-7 pubmed publisher
    ..DNA complex. Data from this study suggest that in general dihalo-substituted analogues have higher potency than monohalo-substituted compounds, but that further addition of halogens is not beneficial. ..
  31. Perryman A, Forli S, Morris G, Burt C, Cheng Y, Palmer M, et al. A dynamic model of HIV integrase inhibition and drug resistance. J Mol Biol. 2010;397:600-15 pubmed publisher
    ..the effects of key drug resistance mutations on the dynamic flexibility and conformational preferences of HIV integrase and to (2) study raltegravir binding in the context of these dynamic models of both wild type and the G140S/..
  32. Balakrishnan M, Yant S, Tsai L, O Sullivan C, Bam R, Tsai A, et al. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS ONE. 2013;8:e74163 pubmed publisher
  33. Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, et al. Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo. Antimicrob Agents Chemother. 2010;54:491-501 pubmed publisher
    ..Altogether our results not only show that the mutation at position Y143 is one of the mechanisms conferring resistance to RAL but also explain the delayed emergence of this mutation. ..
  34. Charpentier C, Roquebert B, Delelis O, Larrouy L, Matheron S, Tubiana R, et al. Hot spots of integrase genotypic changes leading to HIV-2 resistance to raltegravir. Antimicrob Agents Chemother. 2011;55:1293-5 pubmed publisher
    ..Thus, despite a 40% difference in integrase genes between HIV-1 and HIV-2, the genetic pathways leading to raltegravir resistance are similar. ..
  35. Terreni M, Valentini P, Liverani V, Gutierrez M, Di Primio C, Di Fenza A, et al. GCN5-dependent acetylation of HIV-1 integrase enhances viral integration. Retrovirology. 2010;7:18 pubmed publisher
    ..Finally, this study contributes to clarifying the recent debate raised on the role of IN acetylated lysines during HIV-1 infection. ..
  36. Kotova S, Li M, Dimitriadis E, Craigie R. Nucleoprotein intermediates in HIV-1 DNA integration visualized by atomic force microscopy. J Mol Biol. 2010;399:491-500 pubmed publisher
    ..Finally, the integration product remains tightly bound by the integrase tetramer, but the 3' ends of the target DNA in the complex are not restrained and are free to rotate, resulting in relaxation of initially supercoiled target DNA. ..
  37. Ao Z, Danappa Jayappa K, Wang B, Zheng Y, Kung S, Rassart E, et al. Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication. J Virol. 2010;84:8650-63 pubmed publisher
    ..Overall, this study demonstrates for the first time that Impalpha3 is an HIV integrase-interacting cofactor that is required for efficient HIV-1 nuclear import and replication in both dividing and ..
  38. Brenner B, Lowe M, Moisi D, Hardy I, Gagnon S, Charest H, et al. Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors. J Med Virol. 2011;83:751-9 pubmed publisher
    ..These results demonstrate the importance of understanding subtype variability in the development of resistance to INIs. ..
  39. Hare S, Smith S, Metifiot M, Jaxa Chamiec A, Pommier Y, Hughes S, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011;80:565-72 pubmed publisher
    ..In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs. ..
  40. Quashie P, Mesplede T, Han Y, Oliveira M, Singhroy D, Fujiwara T, et al. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol. 2012;86:2696-705 pubmed publisher
    ..Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions. ..
  41. Desimmie B, Schrijvers R, Demeulemeester J, Borrenberghs D, Weydert C, Thys W, et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology. 2013;10:57 pubmed publisher
    LEDGINs are novel allosteric HIV integrase (IN) inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN...
  42. Bar Magen T, Sloan R, Faltenbacher V, Donahue D, Kuhl B, Oliveira M, et al. Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes. Retrovirology. 2009;6:103 pubmed publisher
    ..This suggests that the use of integrase inhibitors against HIV-1 subtype C will result in comparable outcomes to those obtained against subtype B infections. ..
  43. Hu Z, Kuritzkes D. Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness. J Acquir Immune Defic Syndr. 2010;55:148-55 pubmed publisher
    ..These findings correspond well with the clinical trials data and help explain the temporal pattern of RAL resistance evolution. ..
  44. Canducci F, Barda B, Ceresola E, Spagnuolo V, Sampaolo M, Boeri E, et al. Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption. Clin Microbiol Infect. 2011;17:928-34 pubmed publisher
  45. Al Mawsawi L, Neamati N. Allosteric inhibitor development targeting HIV-1 integrase. ChemMedChem. 2011;6:228-41 pubmed publisher
    ..Herein we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active-site regions to inhibit IN function. ..
  46. De Iaco A, Luban J. Inhibition of HIV-1 infection by TNPO3 depletion is determined by capsid and detectable after viral cDNA enters the nucleus. Retrovirology. 2011;8:98 pubmed publisher
    ..TNPO3 promotes HIV-1 infectivity at a step in the virus life cycle that is detectable after the preintegration complex arrives in the nucleus and CA is the viral determinant for TNPO3 dependence. ..
  47. Ebina H, Kanemura Y, Suzuki Y, Urata K, Misawa N, Koyanagi Y. Integrase-independent HIV-1 infection is augmented under conditions of DNA damage and produces a viral reservoir. Virology. 2012;427:44-50 pubmed publisher
    ..Altogether, our results suggest that HIV DNA has integration potential in the presence of an IN inhibitor and may serve as a virus reservoir. ..
  48. Hu G, Li X, Zhang X, Li Y, Ma L, Yang L, et al. Discovery of inhibitors to block interactions of HIV-1 integrase with human LEDGF/p75 via structure-based virtual screening and bioassays. J Med Chem. 2012;55:10108-17 pubmed publisher
    ..These findings could be helpful for anti-HIV drug discovery. ..
  49. Belshan M, Schweitzer C, Donnellan M, Lu R, Engelman A. In vivo biotinylation and capture of HIV-1 matrix and integrase proteins. J Virol Methods. 2009;159:178-84 pubmed publisher
    ..These results therefore establish a system whereby biotinylated matrix protein in the context of replication-competent virus could be used to label and capture viral protein complexes in vivo. ..
  50. Plewe M, Butler S, Dress K, Hu Q, JOHNSON T, Kuehler J, et al. Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors. J Med Chem. 2009;52:7211-9 pubmed publisher
    ..Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors. ..
  51. Garcia Rivera J, Bueno M, Morales E, Kugelman J, Rodriguez D, Llano M. Implication of serine residues 271, 273, and 275 in the human immunodeficiency virus type 1 cofactor activity of lens epithelium-derived growth factor/p75. J Virol. 2010;84:740-52 pubmed publisher
    ..These results clearly indicated that serine residues 271, 273, and 275 influence the HIV-1 cofactor activity of integrase-to-chromatin-tethering-competent LEDGF/p75. ..
  52. Briones M, Dobard C, Chow S. Role of human immunodeficiency virus type 1 integrase in uncoating of the viral core. J Virol. 2010;84:5181-90 pubmed publisher
    ..Taken together, our results indicate that IN is required during uncoating for maintaining CypA-CA interaction, which promotes optimal stability of the viral core. ..
  53. Suzuki S, Urano E, Hashimoto C, Tsutsumi H, Nakahara T, Tanaka T, et al. Peptide HIV-1 integrase inhibitors from HIV-1 gene products. J Med Chem. 2010;53:5356-60 pubmed publisher
    ..The addition of an octa-arginyl group to the inhibitory peptides caused a remarkable inhibition of the strand transfer and 3'-end-processing reactions catalyzed by IN and significant inhibition against HIV replication. ..
  54. Kobayashi M, Yoshinaga T, Seki T, Wakasa Morimoto C, Brown K, Ferris R, et al. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55:813-21 pubmed publisher
    S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster...
  55. Schrijvers R, De Rijck J, Demeulemeester J, Adachi N, Vets S, Ronen K, et al. LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs. PLoS Pathog. 2012;8:e1002558 pubmed publisher
    ..These results further support the potential of LEDGINs as allosteric integrase inhibitors. ..
  56. Boese A, Sommer P, Holzer D, Maier R, Nehrbass U. Integrase interactor 1 (Ini1/hSNF5) is a repressor of basal human immunodeficiency virus type 1 promoter activity. J Gen Virol. 2009;90:2503-12 pubmed publisher
  57. Reuman E, Bachmann M, Varghese V, Fessel W, Shafer R. Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector. Antimicrob Agents Chemother. 2010;54:934-6 pubmed publisher
    ..Investigational integrase inhibitors with activity against these clones are likely to retain activity against the most clinically relevant raltegravir-resistant variants. ..
  58. Zheng Y, Ao Z, Jayappa K, Yao X. Characterization of the HIV-1 integrase chromatin- and LEDGF/p75-binding abilities by mutagenic analysis within the catalytic core domain of integrase. Virol J. 2010;7:68 pubmed publisher
  59. Reigadas S, Masquelier B, Calmels C, Laguerre M, Lazaro E, Vandenhende M, et al. Structure-analysis of the HIV-1 integrase Y143C/R raltegravir resistance mutation in association with the secondary mutation T97A. Antimicrob Agents Chemother. 2011;55:3187-94 pubmed publisher
    ..This result indicates that the emergence of the Y143C/R/T97A double-mutation pattern in patients is a signature of a high resistance level. ..
  60. McNeely M, Hendrix J, Busschots K, Boons E, Deleersnijder A, Gerard M, et al. In vitro DNA tethering of HIV-1 integrase by the transcriptional coactivator LEDGF/p75. J Mol Biol. 2011;410:811-30 pubmed publisher
  61. Ni X, Delelis O, Charpentier C, Storto A, Collin G, Damond F, et al. G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to raltegravir whereas Y143C does not. Retrovirology. 2011;8:68 pubmed publisher
    ..Finally, the Y143C mutation counteracts the resistance conferred by the N155H mutation, probably accounting for the lack of detection of these mutations together in a single genome. ..
  62. Christ F, Debyser Z. The LEDGF/p75 integrase interaction, a novel target for anti-HIV therapy. Virology. 2013;435:102-9 pubmed publisher
    ..In this review we will highlight the research validating the LEDGF/p75-IN interaction as a target for anti-HIV drug discovery and the recent advances in the design and development of LEDGINs. ..
  63. Bojja R, Andrake M, Merkel G, Weigand S, Dunbrack R, Skalka A. Architecture and assembly of HIV integrase multimers in the absence of DNA substrates. J Biol Chem. 2013;288:7373-86 pubmed publisher
    ..and protein cross-linking coupled with mass spectrometry to determine the architectures of full-length HIV integrase (IN) dimers in solution...
  64. Jurado K, Wang H, Slaughter A, Feng L, Kessl J, Koh Y, et al. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc Natl Acad Sci U S A. 2013;110:8690-5 pubmed publisher
    ..The vulnerability of IN to small molecules during the late phase of HIV-1 replication unveils a pharmacological Achilles' heel for exploitation in clinical ALLINI development...
  65. Kessl J, Eidahl J, Shkriabai N, Zhao Z, McKee C, Hess S, et al. An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol Pharmacol. 2009;76:824-32 pubmed publisher
    ..The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN. ..
  66. Passaes C, Guimarães M, Bello G, Morgado M. Near full-length genome characterization of HIV type 1 unique BC recombinant forms from Southern Brazil. AIDS Res Hum Retroviruses. 2009;25:1339-44 pubmed publisher
    ..Our data provide the first description of the near full-length genomes of URFs_BC in Brazil and offer important insights about the complexity of HIV-1 recombinant strains currently in circulation in the south of Brazil. ..
  67. Métifiot M, Maddali K, Naumova A, Zhang X, Marchand C, Pommier Y. Biochemical and pharmacological analyses of HIV-1 integrase flexible loop mutants resistant to raltegravir. Biochemistry. 2010;49:3715-22 pubmed publisher
    ..Our results demonstrate that IN mutations at positions 140 and 148 in the IN flexible loop can account for the phenotype of RAL-resistant viruses. ..
  68. Garrido C, Soriano V, Geretti A, Zahonero N, Garcia S, Booth C, et al. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients--impact of HIV subtypes and prior raltegravir experience. Antiviral Res. 2011;90:164-7 pubmed publisher
    ..T124A was more frequent in INI-naïve patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals. Thus, both HIV-1 subtype and raltegravir exposure may influence the antiviral activity of dolutegravir. ..
  69. Hurt C. Transmitted resistance to HIV integrase strand-transfer inhibitors: right on schedule. Antivir Ther. 2011;16:137-40 pubmed publisher
  70. Telvekar V, Patel K. Pharmacophore development and docking studies of the hiv-1 integrase inhibitors derived from N-methylpyrimidones, Dihydroxypyrimidines, and bicyclic pyrimidinones. Chem Biol Drug Des. 2011;78:150-60 pubmed publisher
    ..The docking studies were also carried out wherein the molecules were docked against the active site of HIV integrase to analyze the binding mode and the necessary structural requirement for their respective enzymatic inhibition...
  71. Katz R, Merkel G, Andrake M, Roder H, Skalka A. Retroviral integrases promote fraying of viral DNA ends. J Biol Chem. 2011;286:25710-8 pubmed publisher
    ..We conclude that frayed ends represent a functional intermediate in which DNA termini can be sampled for suitability for endonucleolytic processing. ..
  72. Gabriel R, Lombardo A, Arens A, Miller J, Genovese P, Kaeppel C, et al. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nat Biotechnol. 2011;29:816-23 pubmed publisher
    ..Comprehensive mapping of ZFN activity in vivo will facilitate the broad application of these reagents in translational research. ..
  73. Malet I, Fourati S, Charpentier C, Morand Joubert L, Armenia D, Wirden M, et al. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother. 2011;66:2827-30 pubmed publisher
    ..This new genetic pathway, never described in subtype B, should be further evaluated for phenotypic susceptibility to dolutegravir and MK-2048. ..
  74. Pandey K, Bera S, Grandgenett D. The HIV-1 integrase monomer induces a specific interaction with LTR DNA for concerted integration. Biochemistry. 2011;50:9788-96 pubmed publisher
    ..The HIV IN monomer may be a suitable candidate for attempting crystallization of an IN-DNA complex in the absence or presence of strand transfer inhibitors. ..
  75. Mantovani N, Azevedo R, Rabelato J, Sanabani S, Diaz R, Komninakis S. Analysis of transmitted resistance to raltegravir and selective pressure among HIV-1-infected patients on a failing HAART in Sao Paulo, Brazil. J Clin Microbiol. 2012;50:2122-5 pubmed publisher
    ..We found a high frequency of integrase polymorphisms related to the resistance to RAL and sequence stability. Further studies are needed to determine the importance of these polymorphisms to RAL resistance. ..
  76. Malet I, Calvez V, Marcelin A. The future of integrase inhibitors of HIV-1. Curr Opin Virol. 2012;2:580-7 pubmed publisher
    ..The place of this class on HIV inhibitors and their future role in perspective of novel therapies to eliminate latent HIV reservoirs and infection for cure should also be explored. ..
  77. Wainberg M, Mesplede T, Quashie P. The development of novel HIV integrase inhibitors and the problem of drug resistance. Curr Opin Virol. 2012;2:656-62 pubmed publisher
  78. Mesplede T, Quashie P, Osman N, Han Y, Singhroy D, Lie Y, et al. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology. 2013;10:22 pubmed publisher
    ..Since H51Y and R263K may define a unique resistance pathway to dolutegravir, our results are consistent with the absence of resistance mutations in antiretroviral drug-naive patients treated with this drug. ..
  79. Quercia R, Dam E, Perez Bercoff D, Clavel F. Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol. 2009;83:10245-9 pubmed publisher
    ..This finding likely explains why N155H can be selected early in the course of RAL resistance evolution in vivo but is later replaced by genotypes that include Q148HKR. ..
  80. Mouscadet J, Arora R, André J, Lambry J, Delelis O, Malet I, et al. HIV-1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations. J Mol Recognit. 2009;22:480-94 pubmed publisher
    Virologic failure during treatment with raltegravir, the first effective drug targeting HIV integrase, is associated with two exclusive pathways involving either Q148H/R/K, G140S/A or N155H mutations...
  81. Fransen S, Gupta S, Danovich R, Hazuda D, Miller M, Witmer M, et al. Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol. 2009;83:11440-6 pubmed publisher
    ..This study demonstrates distinct genetic pathways to resistance in subjects failing raltegravir regimens and defines the effects of primary and secondary resistance mutations on raltegravir susceptibility and replication capacity. ..
  82. Arruda L, Fonseca L, Duarte A, Casseb J. Genetic diversity on the integrase region of the pol gene among HIV type 1-infected patients naive for integrase inhibitors in São Paulo City, Brazil. AIDS Res Hum Retroviruses. 2010;26:105-7 pubmed publisher
    ..The impact of these findings remains unclear and further studies are necessary to address these questions. ..
  83. Ferris A, Wu X, Hughes C, Stewart C, Smith S, Milne T, et al. Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration. Proc Natl Acad Sci U S A. 2010;107:3135-40 pubmed publisher
    ..The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy. ..
  84. Fitzkee N, Masse J, Shen Y, Davies D, Bax A. Solution conformation and dynamics of the HIV-1 integrase core domain. J Biol Chem. 2010;285:18072-84 pubmed publisher
    ..Indeed, automated chemical shift-based modeling of the active site loop reveals several stable clusters that show striking similarity to a recent crystal structure of prototype foamy virus IN bound to DNA. ..
  85. Gupta K, Diamond T, Hwang Y, Bushman F, Van Duyne G. Structural properties of HIV integrase. Lens epithelium-derived growth factor oligomers. J Biol Chem. 2010;285:20303-15 pubmed publisher
    ..These IN oligomers may be involved in stages of the viral life cycle other than integration, including assembly, budding, and early replication. ..
  86. Bar Magen T, Sloan R, Donahue D, Kuhl B, Zabeida A, Xu H, et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol. 2010;84:9210-6 pubmed publisher
  87. De Luca L, Ferro S, Gitto R, Barreca M, Agnello S, Christ F, et al. Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg Med Chem. 2010;18:7515-21 pubmed publisher
    ..The results obtained demonstrate that the hydrophobic pocket could play a key role in improving inhibitory efficacy thus opening new suggestions to design active ligands. ..
  88. Liao C, Marchand C, Burke T, Pommier Y, Nicklaus M. Authentic HIV-1 integrase inhibitors. Future Med Chem. 2010;2:1107-22 pubmed publisher
    ..Current and future attention will be focused on the development of novel authentic IN inhibitors with the goal of overcoming viral resistance. ..
  89. Rhodes D, Peat T, Vandegraaff N, Jeevarajah D, Newman J, Martyn J, et al. Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site. Chembiochem. 2011;12:2311-5 pubmed publisher
    ..We investigated the crystallographic complexes of the HIV integrase (HIV-IN) catalytic core domain with 13 of the peptides and identified multiple interactions at the binding ..
  90. Odintsova E, Baranova S, Dmitrenok P, Rasskazov V, Calmels C, Parissi V, et al. Antibodies to HIV integrase catalyze site-specific degradation of their antigen. Int Immunol. 2011;23:601-12 pubmed publisher
    ..Since anti-IN IgGs and IgMs can efficiently hydrolyze IN, a positive role of the Abzs in counteracting the infection is possible. ..
  91. Demeulemeester J, Tintori C, Botta M, Debyser Z, Christ F. Development of an AlphaScreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors. J Biomol Screen. 2012;17:618-28 pubmed publisher
    ..Compounds identified as hits in this assay proved to act as allosteric IN inhibitors. Additionally, the assay offers a flexible platform to study IN dimerization. ..
  92. Hu G, Li X, Sun X, Lu W, Liu G, Huang J, et al. Identification of old drugs as potential inhibitors of HIV-1 integrase - human LEDGF/p75 interaction via molecular docking. J Mol Model. 2012;18:4995-5003 pubmed publisher
    ..This work provides a new example of inhibitors targeting protein-protein interaction and confirmed that old drugs were valuable sources for antiviral drug discovery. ..