1887

Chapter 5 : Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815493/9781555814397_Chap05-1.gif /docserver/preview/fulltext/10.1128/9781555815493/9781555814397_Chap05-2.gif

Abstract:

This chapter describes the unique role of integrase (IN) in the human immunodeficiency virus type 1 (HIV-1) replication cycle and its interaction with different cellular proteins. It addresses the efficacy and toxicity data of the new drugs targeting IN, along with their biochemical, pharmacokinetic, and pharmacodynamic characteristics. It also discusses clinical perspectives and viral resistance against IN inhibitors as well as recently identified new antiviral targets in HIV IN. Since retroviral integration is a multistep process, the different cofactors can theoretically play a role during one of the following steps: (i) catalysis, (ii) nuclear import of the PIC, (iii) target site selection, and (iv) repair of the DNA gaps. The chapter gives an overview of the search for HIV-1 IN inhibitors, and discusses current IN inhibitors in clinical development. The major mechanism of clearance of MK-0518 (raltegravir) in humans is UDP-glucuronyltransferase (UGT) isoform, 1A1-mediated glucuronidation. In a multicenter, double-blind, randomized study (MK-0518 protocol 005), the safety and efficacy of MK-0518 versus placebo, both regimens also using optimized background therapy (OBT), were evaluated. This study was designed to include highly antiretroviral therapy (ART)-experienced patients with a documented genotypic/phenotypic resistance for more than one drug in each of the three classes (NNRTI, NRTI, and PI) with HIV RNA levels of >5,000 copies and CD4 counts of >50 cells/mm. Resistance to IN inhibitors has been relatively well defined for a new class of antiretroviral agents. IN has only been recently validated in clinical trials as a target for antiretroviral therapy.

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5

Key Concept Ranking

Non-Nucleoside Reverse Transcriptase Inhibitors
0.507514
Reverse Transcriptase Inhibitors
0.5016682
Human immunodeficiency virus 1
0.48606855
Highly Active Antiretroviral Therapy
0.4024222
0.507514
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 1.
Figure 1.

(A) HIV IN. HIV-1 IN is a 288-amino-acid protein (32 kDa) that is encoded by the 3’ end of the HIV gene. IN contains three distinct functional domains. The N-terminal domain (amino acids 1 through 50) is believed to be involved in protein multimerization. The central or catalytic core domain (CCD) spanning amino acids 51 through 212 contains the catalytic triad consisting of aspartic acid (Asp-D) 64, Asp (D) 116, and glutamic acid (E) 152, a classical DDE. The less conserved C-terminal domain of IN (amino acids 213 through 288) has nonspecific but strong DNA binding activity, similar to that of the full-length IN. (B) Model of HIV IN binding the viral DNA. This model ( ) shows the binding of the viral DNA to HIV-1 IN in the cytoplasm. Most probably HIV-1 IN acts as a dimer with each monomer capable of binding one end of the viral DNA. (C) Model of HIV IN binding after the 3’ processing step. After reverse transcription, IN removes a pGT dinucleotide at each 3’ end of the viral LTRs adjacent to a highly conserved CA dinucleotide ( ). The binding of the viral DNA to IN after the 3’ processing is shown in this model.

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

The HIV-1 replication cycle and potential drugs targeting the integration process. The respective drugs and their mechanisms of action are noted under each step of the integration process: strand transfer inhibitors and 3’ processing inhibitors. The viral RNA is transcribed into double-stranded DNA during reverse transcription. Double-stranded DNA forms can be quantified by PCR. IN binds to specific sequences in the LTR region of viral DNA, which results in stable viral DNA IN complex formation. IN-DNA binding inhibitors such as pyranodipyrimidines and styrylquinolines can inhibit this step. The PIC is a cytoplasmic, virally derived, nucleoprotein structure that contains RT, IN, matrix, and nucleocapsid. In the following step the PIC is transported to the nucleus. IN removes a pGT dinucleotide at each end of the viral DNA LTRs producing new 3’-hydroxyl ends (CA-3’-OH). 3’ Processing inhibitors such as styrylquinolines do interfere with LTR/IN binding through a competitive inhibition mechanism. In the next step IN binds to the host chromosomal DNA and mediates a concerted nucleophilic attack by the 3’-hydroxyl residues of the viral DNA on phosphodiester bridges in the target DNA. The processed CA-3’-OH viral DNA ends are ligated to the 5’--phosphate ends of the target DNA, covalently attaching the viral DNA to the cellular DNA. Strand transfer inhibitors such as MK-0518 and GS-9137 interfere with this step. Through the unproductive pathways of DNA circularization, 1- and 2-LTR circles are made in the nucleus. The number of 2-LTR circles serves as a quantitative measurement for nuclear import in the absence of an inhibitor of strand transfer. The number of 2-LTR circles increases by interfering with the strand transfer reaction or by inhibition of the LEDGF/p75-IN interaction. During the following gap repair, the reaction intermediate will be repaired. This is accomplished by host cell DNA repair enzymes. Finally, a Q-PCR assay using primer annealing to repetitive host cell DNA (e.g., Alu sequence) and one primer annealing to the viral DNA allows quantification of integrated viral DNA ( ).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3.
Figure 3.

Domain structure of LEDGF/p75. The p75 and p52 splice variants are indicated. LEDGF/p75 contains 530 amino acids and several functional domains. In the N-terminal part of LEDGF/p75 the PWWP domain of 92 residues functions as a protein-protein interaction domain ( ) and/or DNA-binding domain ( ). A functional nuclear localization signal (NLS), GRKRKAEKQ (amino acids 148 to 156), is present ( ). In accord with its ability to interact with HIV-1 IN, an evolutionary conserved IBD of approximately 80 amino acids (amino acids 347 to 429) was recently mapped to the C terminus ( ).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4.
Figure 4.

Results of all phase II and III clinical trials performed with MK-0518. (A) Protocol 004, evaluation of the safety and efficacy of MK-0518 in naive patients. In the MK-0518 protocol 004, patients received tenofovir + 3TC as backbone, combined with 100 mg ( = 39), 200 mg ( = 40), 400 mg ( = 41), or 600 mg ( = 40) of MK-0518 twice daily (b.i.d.) or 600 mg of efavirenz ( = 38) once daily (q.d.) in the control arm in a double-blinded trial. (B) Results of protocol 005, evaluation of the safety and efficacy of MK-0518 in multiresistant patients. In the MK-0518 protocol 005, the safety and efficacy of MK-0518 (200, 400, or 600 mg orally twice daily) compared to placebo, both with OBT, were evaluated in a multicenter, double-blind, randomized study in multiresistant patients. The percentage of patients with HIV RNA levels of <50 copies/ml is shown over a period of at least 24 weeks. (C and D) Results of BENCHMRK-1 (C) and of BENCHMRK-2 (D) studies. The addition of raltegravir to standard of care in heavily treatment-experienced patients was evaluated. The percentage of patients with HIV RNA levels of <50 copies/ml is shown over a period of 24 weeks.

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 5.
Figure 5.

Evaluation of the antiviral activity and safety of GS-9137. The antiviral activity and safety of GS-9137 were evaluated in a prospective, randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1-infected treatment-naive and -experienced patients ( ). GS-9137 was administered with food for 10 days at a dose of 200, 400, or 800 mg twice daily, 800 mg once daily, or 50 mg boosted with 100 mg of RTV once daily (six subjects taking active drugs and two taking placebo per cohort).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 6.
Figure 6.

Mutations at 29 positions on HIV-1 that may reduce susceptibility to IN inhibitors ( ).

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555815493.ch05
1. Anderson, M. S.,, T. N. Kakuda,, W. Hanley,, J. Miller,, J. T. Kost,, R. Stoltz,, L. A. Wenning,, J. A. Stone,, R. M. Hoetelmans,, J. A. Wagner, and, M. Iwamoto. 2008. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob. Agents Chemother. 52:42284232.
2. Aono, S.,, Y. Yamada,, H. Keino,, N. Hanada,, T. Nakagawa,, Y. Sasaoka,, T. Yazawa,, H. Sato, and, O. Koiwai. 1993. Identification of defect in the genes for bilirubin UDP-glucuronosyl-transferase in a patient with Crigler-Najjar syndrome type II. Biochem. Biophys. Res. Commun. 197:12391244.
3. Arkin, M. R., and, J. A. Wells. 2004. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat. Rev. Drug Discov. 3:301317.
4. Bartholomeeusen, K.,, J. De Rijck,, K. Busschots,, L. Desender,, R. Gijsbers,, S. Emiliani,, R. Benarous,, Z. Debyser, and, F. Christ. 2007. Differential interaction of HIV-1 integrase and JPO2 with the C terminus of LEDGF/p75. J. Mol. Biol. 372:407421.
5. Beitzel, B., and, F. Bushman. 2003. Construction and analysis of cells lacking the HMGA gene family. Nucleic Acids Res. 31:50255032.
6. Billich, A. 2003. S-1360 Shionogi-GlaxoSmithKline. Curr. Opin. Investig. Drugs 4:206209.
7. Bonnenfant, S.,, C. M. Thomas,, C. Vita,, F. Subra,, E. Deprez,, F. Zouhiri,, D. Desmaele,, J. D’Angelo,, J. F. Mouscadet, and, H. Leh. 2004. Styrylquinolines, integrase inhibitors acting prior to integration: a new mechanism of action for anti-integrase agents. J. Virol. 78:57285736.
8. Borst, P.,, C. de Wolf, and, K. van de Wetering. 2006. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 453:661673.
9. Bosma, P. J.,, J. R. Chowdhury,, C. Bakker,, S. Gantla,, A. de Boer,, B. A. Oostra,, D. Lindhout,, G. N. Tytgat,, P. L. Jansen,, R. P. Oude Elferink, et al. 1995. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N. Engl. J. Med. 333:11711175.
10. Bushman, F. D. 2003. Targeting survival: integration site selection by retroviruses and LTR-retrotransposons. Cell 115:135138.
11. Busschots, K.,, J. Vercammen,, S. Emiliani,, R. Benarous,, Y. Engel-borghs,, F. Christ, and, Z. Debyser. 2005. The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J. Biol. Chem. 280:1784117847.
12. Butler, S. L.,, M. S. Hansen, and, F. D. Bushman. 2001. A quantitative assay for HIV DNA integration in vivo. Nat. Med. 7:631634.
13. Cai, M.,, R. Zheng,, M. Caffrey,, R. Craigie,, G. M. Clore, and, A. M. Gronenborn. 1997. Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. Nat. Struct. Biol. 4:567577.
14. Cereseto, A.,, L. Manganaro,, M. I. Gutierrez,, M. Terreni,, A. Fittipaldi,, M. Lusic,, A. Marcello, and, M. Giacca. 2005. Acetylation of HIV-1 integrase by p300 regulates viral integration. EMBO J. 24:30703081.
15. Chen, H., and, A. Engelman. 1998. The barrier-to-autointegration protein is a host factor for HIV type 1 integration. Proc. Natl. Acad. Sci. USA 95:1527015274.
16. Chen, J. C.,, J. Krucinski,, L. J. Miercke,, J. S. Finer-Moore,, A. H. Tang,, A. D. Leavitt, and, R. M. Stroud. 2000. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proc. Natl. Acad. Sci. USA 97:82338238.
17. Cherepanov, P.,, A. L. Ambrosio,, S. Rahman,, T. Ellenberger, and, A. Engelman. 2005. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl. Acad. Sci. USA 102:1730817313.
18. Cherepanov, P.,, E. Devroe,, P. A. Silver, and, A. Engelman. 2004. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J. Biol. Chem. 279:4888348892.
19. Cherepanov, P.,, G. Maertens,, P. Proost,, B. Devreese,, J. Van Beeumen,, Y. Engelborghs,, E. De Clercq, and, Z. Debyser. 2003. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278:372381.
20. Cherepanov, P.,, Z. Y. Sun,, S. Rahman,, G. Maertens,, G. Wagner, and, A. Engelman. 2005. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat. Struct. Mol. Biol. 12:526532.
21. Chiu, T. K., and, D. R. Davies. 2006. Structure and function of HIV-1 integrase: an update. Front. Med. Chem. 3:322.
22. Ciuffi, A.,, M. Llano,, E. Poeschla,, C. Hoffmann,, J. Leipzig,, P. Shinn,, J. R. Ecker, and, F. Bushman. 2005. A role for LEDGF/p75 in targeting HIV DNA integration. Nat. Med. 11:12871289.
23. Colombo, S.,, N. Soranzo,, M. Rotger,, R. Sprenger,, G. Bleiber,, H. Furrer,, T. Buclin,, D. Goldstein,, L. Decosterd, and, A. Telenti. 2005. Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplo-types on the cellular exposure of nelfinavir in vivo. Pharmacogenet. Genomics 15:599608.
24. [Reference deleted.]
25. Cuevas, M.,, L. Perez-Alvarez,, M. Sierra,, M. Munoz,, E. Delgado,, Y. Vega,, M. Thomson,, G. Contreras, and, R. Najera. 2007. Low frequency of natural resistance-associated mutations to integrase inhibitors in HIV-1 infected patients. 5th Eur. HIV Drug Resist. Workshop, Cascais, Portugal.
26. Danska, J. S.,, D. P. Holland,, S. Mariathasan,, K. M. Williams, and, C. J. Guidos. 1996. Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes. Mol. Cell. Biol. 16:55075517.
27. Debyser, Z.,, P. Cherepanov,, B. Van Maele,, E. De Clercq, and, M. Witvrouw. 2002. In search of authentic inhibitors of HIV-1 integration. Antivir. Chem. Chemother. 13:115.
28. DeJesus, E.,, D. Berger,, M. Markowitz,, C. Cohen,, T. Hawkins,, P. Ruane,, R. Elion,, C. Farthing,, L. Zhong,, A. K. Cheng,, D. McColl, and, B. P. Kearney. 2006. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 43:15.
29. DeJesus, E.,, D. B.,, M Markowitz,, C. Cohen,, T. Hawkins,, P. Ruane,, R. Elion,, C. Farthing,, A. Cheng,, B. Kearney, and the 183–0101 Study Team. 2006. The HIV integrase inhibitor GS-9137 (JTK-303) exhibits potent antiviral activity in treatment-naïve and experienced patients. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO.
30. De Rijck, J.,, L. Vandekerckhove,, R. Gijsbers,, A. Hombrouck,, J. Hendrix,, J. Vercammen,, Y. Engelborghs,, F. Christ, and, Z. Debyser. 2006. Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J. Virol. 80:1149811509.
31. Devroe, E., and, P. A. Silver. 2002. Retrovirus-delivered siRNA. BMC Biotechnol. 2:15.
32. Dicker, I. B.,, H. K. Samanta,, Y. Hong,, Y. Tian,, J. Banville,, R. R. Remillard,, M. A. Walker,, D. R. Langley, and, M. R. Krystal. 2007. Changes to the HIV LTR and to HIV integrase differentially impact HIV integrase assembly, activity and the binding of strand transfer inhibitors. J. Biol. Chem. 282:3118631196.
33. Dietz, F.,, S. Franken,, K. Yoshida,, H. Nakamura,, J. Kappler, and, V. Gieselmann. 2002. The family of hepatoma-derived growth factor proteins: characterization of a new member HRP-4 and classification of its subfamilies. Biochem. J. 366:491500.
34. Dupuis, M. L.,, M. Cianfriglia,, R. Costi,, C. Galluzzo,, M. Andreotti,, A. Roux,, R. Di Santo, and, L. Palmisano. 2006. HIV-1 Integrase Inhibitors Are Potent Substrates for the MDR1 Multidrug Transporter. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO.
35. Dyda, F.,, A. B. Hickman,, T. M. Jenkins,, A. Engelman,, R. Craigie, and, D. R. Davies. 1994. Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transfer-ases. Science 266:19811986.
36. Eijkelenboom, A. P.,, R. A. Lutzke,, R. Boelens,, R. H. Plasterk,, R. Kaptein, and, K. Hard. 1995. The DNA-binding domain of HIV-1 integrase has an SH3-like fold. Nat. Struct. Biol. 2:807810.
37. Emiliani, S.,, A. Mousnier,, K. Busschots,, M. Maroun,, B. Van Maele,, D. Tempe,, L. Vandekerckhove,, F. Moisant,, L. Ben-Slama,, M. Witvrouw,, F. Christ,, J. C. Rain,, C. Dargemont,, Z. Debyser, and, R. Benarous. 2005. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J. Biol. Chem. 280:2551725523.
38. Engelman, A., and, R. Craigie. 1992. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J. Virol. 66:63616369.
39. Engelman, A.,, G. Englund,, J. M. Orenstein,, M. A. Martin, and, R. Craigie. 1995. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J. Virol. 69:27292736.
40. Engelman, A.,, K. Mizuuchi, and, R. Craigie. 1991. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell 67:12111221.
41. Espeseth, A. S.,, P. Felock,, A. Wolfe,, M. Witmer,, J. Grobler,, N. Anthony,, M. Egbertson,, J. Y. Melamed,, S. Young,, T. Hamill,, J. L. Cole, and, D. J. Hazuda. 2000. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl. Acad. Sci. USA 97:1124411249.
42. Esposito, D., and, R. Craigie. 1999. HIV integrase structure and function. Adv. Virus Res. 52:319333.
43. Farnet, C. M., and, F. D. Bushman. 1997. HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro. Cell 88:483492.
44. Farnet, C. M., and, W. A. Haseltine. 1990. Integration of human immunodeficiency virus type 1 DNA in vitro. Proc. Natl. Acad. Sci. USA 87:41644168.
45. Fellay, J.,, C. Marzolini,, E. R. Meaden,, D. J. Back,, T. Buclin,, J. P. Chave,, L. A. Decosterd,, H. Furrer,, M. Opravil,, G. Pantaleo,, D. Retelska,, L. Ruiz,, A. H. Schinkel,, P. Vernazza,, C. B. Eap, and, A. Telenti. 2002. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359:3036.
46. Fikkert, V.,, A. Hombrouck,, B. Van Remoortel,, M. De Maeyer,, C. Pannecouque,, E. De Clercq,, Z. Debyser, and, M. Witvrouw. 2004. Multiple mutations in human immunodeficiency virus-1 integrase confer resistance to the clinical trial drug S-1360. AIDS 18:20192028.
47. Fikkert, V.,, B. Van Maele,, J. Vercammen,, A. Hantson,, B. Van Remoortel,, M. Michiels,, C. Gurnari,, C. Pannecouque,, M. De Maeyer,, Y. Engelborghs,, E. De Clercq,, Z. Debyser, and, M. Witvrouw. 2003. Development of resistance against diketo derivatives of human immunodeficiency virus type 1 by progressive accumulation of integrase mutations. J. Virol. 77:1145911470.
48. Fry, D. C. 2006. Protein-protein interactions as targets for small molecule drug discovery. Biopolymers 84:535552.
49. Ganapathy, V., and, C. A. Casiano. 2004. Autoimmunity to the nuclear autoantigen DFS70 (LEDGF): what exactly are the autoantibodies trying to tell us? Arthritis Rheum. 50:684688.
50. Ge, H.,, Y. Si, and, R. G. Roeder. 1998. Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation. EMBO J. 17:67236729.
51. Grinsztejn, B.,, B. Y. Nguyen,, C. Katlama,, J. M. Gatell,, A. Lazzarin,, D. Vittecoq,, C. J. Gonzalez,, J. Chen,, C. M. Harvey, and, R. D. Isaacs. 2007. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 369:12611269.
52. Grinsztejn, B.,, C. Katlama,, J. Gatell,, A. Lazzarin,, D. Vittecoq,, C. Gonzalez,, J. Chen,, R. Isaacs, and the Protocol 005 Study Team. 2006. Potent antiretroviral effect of MK-0518, a novel hiv-1 integrase inhibitor, in patients with triple-class resistant virus. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO.
53. Grobler, J. A.,, K. Stillmock,, B. Hu,, M. Witmer,, P. Felock,, A. S. Espeseth,, A. Wolfe,, M. Egbertson,, M. Bourgeois,, J. Melamed,, J. S. Wai,, S. Young,, J. Vacca, and, D. J. Hazuda. 2002. Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. USA 99:66616666.
54. Hardcastle, I. R.,, S. U. Ahmed,, H. Atkins,, G. Farnie,, B. T. Golding,, R. J. Griffin,, S. Guyenne,, C. Hutton,, P. Kallblad,, S. J. Kemp,, M. S. Kitching,, D. R. Newell,, S. Norbedo,, J. S. Northen,, R. J. Reid,, K. Saravanan,, H. M. Willems, and, J. Lunec. 2006. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. J. Med. Chem. 49:62096221.
55. Hazuda, D. J.,, N. J. Anthony,, R. P. Gomez,, S. M. Jolly,, J. S. Wai,, L. Zhuang,, T. E. Fisher,, M. Embrey,, J. P. Guare, Jr.,, M. S. Egbertson,, J. P. Vacca,, J. R. Huff,, P. J. Felock,, M. V. Witmer,, K. A. Still-mock,, R. Danovich,, J. Grobler,, M. D. Miller,, A. S. Espeseth,, L. Jin,, I. W. Chen,, J. H. Lin,, K. Kassahun,, J. D. Ellis,, B. K. Wong,, W. Xu,, P. G. Pearson,, W. A. Schleif,, R. Cortese,, E. Emini,, V. Summa,, M. K. Holloway, and, S. D. Young. 2004. A naphthyridine carbox-amide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl. Acad. Sci. USA 101:1123311238.
56. Hazuda, D. J.,, P. Felock,, M. Witmer,, A. Wolfe,, K. Stillmock,, J. A. Grobler,, A. Espeseth,, L. Gabryelski,, W. Schleif,, C. Blau, and, M. D. Miller. 2000. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287:646650.
57. Hazuda, D. J.,, J. C. Hastings,, A. L. Wolfe, and, E. A. Emini. 1994. A novel assay for the DNA strand-transfer reaction of HIV-1 integrase. Nucleic Acids Res. 22:11211122.
58. Hazuda, D. J.,, S. D. Young,, J. P. Guare,, N. J. Anthony,, R. P. Gomez,, J. S. Wai,, J. P. Vacca,, L. Handt,, S. L. Motzel,, H. J. Klein,, G. Dornadula,, R. M. Danovich,, M. V. Witmer,, K. A. Wilson,, L. Tussey,, W. A. Schleif,, L. S. Gabryelski,, L. Jin,, M. D. Miller,, D. R. Casimiro,, E. A. Emini, and, J. W. Shiver. 2004. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 305:528532.
59. Hoffmeyer, S.,, O. Burk,, O. von Richter,, H. P. Arnold,, J. Brock-moller,, A. Johne,, I. Cascorbi,, T. Gerloff,, I. Roots,, M. Eichelbaum, and, U. Brinkmann. 2000. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA 97:34733478.
60. Hombrouck, A.,, J. De Rijck,, J. Hendrix,, L. Vandekerckhove,, A. Voet,, M. De Maeyer,, M. Witvrouw,, Y. Engelborghs,, F. Christ,, R. Gijsbers, and, Z. Debyser. 2007. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog. 3:e47.
61. Iwamoto, M.,, L. A. Wenning,, A. R. Moreau, et al. 2008. Omeprazole increases plasma levels of raltegravir in healthy subjects, abstr. A-963. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother., Washington, DC, October 2008.
62. Iwamoto, M.,, L. A. Wenning, and, A. S. Petry. 2006. Minimal effect of ritonavir (RTV) and efavirenz (EFV) on the pharmacokinetics (PK) of Mk-0518, abstr. A-373. 46th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA.
63. Iwamoto, M.,, L. A. Wenning,, A. S. Petry,, M. Laethem,, M. De Smet,, J. T. Kost,, S. A. Merschman,, K. M. Strohmaier,, S. Ramael,, K. C. Lasseter,, J. A. Stone,, K. M. Gottesdiener, and, J. A. Wagner. 2008. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin. Pharmacol. Ther. 83:293299.
64. Iwamoto, M.,, L. A. Wenning,, S. Y. Liou,, J. T. Kost,, E. Mangin,, K. M. Strohmaier,, T. C. Marbury,, J. Stone,, K. M. Gottesdiener, and, J. A. Wagner. 2006. Rifampin (RIF) modestly reduces plasma levels of MK-0518, abstr. P299. Abstr. 8th Int. Cong. Drug Ther. HIV Infect., Glasgow, United Kingdom.
65. Iwamoto, M.,, L. A. Wenning,, M. D. Troyer,, J. I. Ventura,, J. T. Kost,, E. Mangin,, K. M. Strohmaier,, E. P. DeNoia,, J. Stone,, K. M. Gottesdiener, and, J. A. Wagner. 2006. Lack of a pharmacokinetic interaction of MK-0518 on midazolam (MDZ), abstr. P300. Int. Cong. Drug Ther. HIV 2006, Glasgow, United Kingdom.
66. Jacque, J. M., and, M. Stevenson. 2006. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Nature 441:581582.
67. Jedlitschky, G.,, I. Leier,, U. Buchholz,, J. Hummel-Eisenbeiss,, B. Burchell, and, D. Keppler. 1997. ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2. Biochem. J. 327(Pt. 1):305310.
68. Johnson, M. S.,, M. A. McClure,, D. F. Feng,, J. Gray, and, R. F. Doolittle. 1986. Computer analysis of retroviral pol genes: assignment of enzymatic functions to specific sequences and homologies with nonviral enzymes. Proc. Natl. Acad. Sci. USA 83:76487652.
69. Jones, G.,, R. Ledford,, F. Yu,, M. Miller,, M. Tsiang, and, D. McColl. 2007. Resistance profile of HIV-1 mutants in vitro selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303), 13th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA.
70. Jones, K. S.,, J. Coleman,, G. W. Merkel,, T. M. Laue, and, A. M. Skalka. 1992. Retroviral integrase functions as a multimer and can turn over catalytically. J. Biol. Chem. 267:1603716040.
71. Kalpana, G. V.,, S. Marmon,, W. Wang,, G. R. Crabtree, and, S. P. Goff. 1994. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science 266:20022006.
72. Kassahun, K.,, I. McIntosh,, D. Cui,, D. Hreniuk,, S. Merschman,, K. Lasseter,, N. Azrolan,, M. Iwamoto,, J. A. Wagner, and, L. A. Wenning. 2007. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab. Dispos. 35:16571663.
73. Kassahun, K.,, I. McIntosh,, D. Hreniuk, et al. 2006. Absorption, metabolism and excretion of MK-0518, a potent HIV-1 integrase inhibitor, in healthy male volunteers, abstr. A-0372. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA.
74. Kawaguchi, I.,, T. Ishikawa,, M. Ishibashi,, S. Irie, and, A. Kakee. 2006. Safety and pharmacokinetics of single oral dose of JTK-303/GS 9137, a novel HIV integrase inhibitor, in healthy volunteers. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO.
75. Koiwai, O.,, M. Nishizawa,, K. Hasada,, S. Aono,, Y. Adachi,, N. Mamiya, and, H. Sato. 1995. Gilbert’s syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDPglucuronosyltransferase. Hum. Mol. Genet. 4:11831186.
76. Lamba, J.,, V. Lamba, and, E. Schuetz. 2005. Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr. Drug Metab. 6:369383.
77. Leavitt, A. D.,, G. Robles,, N. Alesandro, and, H. E. Varmus. 1996. Human immunodeficiency virus type 1 integrase mutants retain in vitro integrase activity yet fail to integrate viral DNA efficiently during infection. J. Virol. 70:721728.
78. Lee, M. S., and, R. Craigie. 1994. Protection of retroviral DNA from autointegration: involvement of a cellular factor. Proc. Natl. Acad. Sci. USA 91:98239827.
79. Leschziner, G.,, D. Zabaneh,, M. Pirmohamed,, A. Owen,, J. Rogers,, A. J. Coffey,, D. J. Balding,, D. B. Bentley, and, M. R. Johnson. 2006. Exon sequencing and high-resolution haplotype analysis of ABC transporter genes implicated in drug resistance. Pharmacogenet. Genomics 16:439450.
80. Llano, M.,, S. Delgado,, M. Vanegas, and, E. M. Poeschla. 2004. LEDGF/p75 prevents proteasomal degradation of HIV-1 integrase. J. Biol. Chem. 8:8.
81. Llano, M.,, D. T. Saenz,, A. Meehan,, P. Wongthida,, M. Peretz,, W. H. Walker,, W. Teo, and, E. M. Poeschla. 2006. An essential role for LEDGF/p75 in HIV integration. Science 314:461464.
82. Llano, M.,, M. Vanegas,, O. Fregoso,, D. Saenz,, S. Chung,, M. Peretz, and, E. M. Poeschla. 2004. LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. J. Virol. 78:95249537.
83. Lutzke, R. A., and, R. H. Plasterk. 1998. Structure-based mutational analysis of the C-terminal DNA-binding domain of human immunodeficiency virus type 1 integrase: critical residues for protein oligomerization and DNA binding. J. Virol. 72:48414848.
84. Maertens, G.,, P. Cherepanov,, Z. Debyser,, Y. Engelborghs, and, A. Engelman. 2004. Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase (IN) inter-actor LEDGF/p75. J. Biol. Chem. 25:25.
85. Maertens, G.,, P. Cherepanov,, W. Pluymers,, K. Busschots,, E. De Clercq,, Z. Debyser, and, Y. Engelborghs. 2003. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 278:3352833539.
86. Maertens, G.,, J. Vercammen,, Z. Debyser, and, Y. Engelborghs. 2005. Measuring protein-protein interactions inside living cells using single color fluorescence correlation spectroscopy. Application to human immunodeficiency virus type 1 integrase and LEDGF/p75. FASEB J. 19:10391041.
87. Maertens, G. N.,, P. Cherepanov, and, A. Engelman. 2006. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J. Cell Sci. 119:25632571.
88. Malet, I.,, L. Fabeni,, C. de Mendoza,, S. Dimonte,, S. Bono,, V. Svicher,, R. D’Arrigo,, P. Flandre,, A. Antinori,, A. D’Arminio Monforte,, C. Katlama,, V. Soriano,, V. Calvez,, C. Perno,, A.-G. Marcelin, and, F. Ceccherini-Silberstein. 2007. Specific mutations associated with in-vitro resistance to HIV-1 integrase inhibitors are present in untreated and NRTI/NNRTI/PI-treated HIV-1 infected patients. 5th European HIV Drug Resistance Workshop, Cascais, Portugal.
89. Margalit, A.,, M. Segura-Totten,, Y. Gruenbaum, and, K. L. Wilson. 2005. Barrier-to-autointegration factor is required to segregate and enclose chromosomes within the nuclear envelope and assemble the nuclear lamina. Proc. Natl. Acad. Sci. USA 102:32903295.
90. Markowitz, M.,, J. O. Morales-Ramirez,, B. Y. Nguyen,, C. M. Kovacs,, R. T. Steigbigel,, D. A. Cooper,, R. Liporace,, R. Schwartz,, R. Isaacs,, L. R. Gilde,, L. Wenning,, J. Zhao, and, H. Teppler. 2006. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. 43:509515.
91. Markowitz, M.,, B. Y. Nguyen,, E. Gotuzzo,, F. Mendo,, W. Ratanasuwan,, C. Kovacs,, G. Prada,, J. O. Morales-Ramirez,, C. S. Crumpacker,, R. D. Isaacs,, L. R. Gilde,, H. Wan,, M. D. Miller,, L. A. Wenning, and, H. Teppler. 2007. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J. Acquir. Immune Defic. Syndr. 46:125133.
92. Masuda, T.,, V. Planelles,, P. Krogstad, and, I. S. Chen. 1995. Genetic analysis of human immunodeficiency virus type 1 integrase and the U3 att site: unusual phenotype of mutants in the zinc finger-like domain. J. Virol. 69:66876696.
93. Mathias, A., et al. 2007. Effect of atazanavir/r on the steady-state pharmacokinetics of elvitegravir, abstr. A-1417. Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL.
94. Mathias, A., et al. 2007. A pharmacokinetic interaction between lopinavir/r and elvitegravir. Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL.
95. Matsuzaki, Y.,, W. Watanabe,, K. Yamataka, et al. 2006. JTK-303/GS-9137, a novel small molecule inhibitor of HIV-1 integrase: anti-HIV activity profile and pharmacokinetics in animals. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO.
96. Mekouar, K.,, J. F. Mouscadet,, D. Desmaele,, F. Subra,, H. Leh,, D. Savoure,, C. Auclair, and, J. d’Angelo. 1998. Styrylquinoline derivatives: a new class of potent HIV-1 integrase inhibitors that block HIV-1 replication in CEM cells. J. Med. Chem. 41:28462857.
97. Miller, M.,, M. Witmer,, K. Stillmock,, P. Felock,, L. Ecto,, J. Flynn,, W. Schleif,, G. Dornadula,, R. Danovich, and, D. Hazuda. 2006. Biochemical and antiviral activity of MK-0518, a potent HIV integrase inhibitor, abstr. THAA0032. XVI Int. AIDS Conf., Toronto, Canada.
98. Miller, M. D., and, F. D. Bushman. 1995. HIV integration. Ini1 for integration? Curr. Biol. 5:368370.
99. Mistry, G. C., W. A.,, S. Merschman,, J. T. Kost,, W. E. Bridson,, J. A. Stone,, K. M. Gottesdiener,, J. A. Wagner, and, M. Iwamoto. 2006. Atazanavir and ritonavir increase plasma levels of MK-0518. 8th International Congress on Drug Therapy and HIV Infection, Glasgow, United Kingdom.
100. Nagar, S., and, R. L. Blanchard. 2006. Pharmacogenetics of uridine diphosphoglucuronosyltransferase (UGT) 1A family members and its role in patient response to irinotecan. Drug Metab. Rev. 38:393409.
101. Nakamura, T.,, T. Masuda,, T. Goto,, K. Sano,, M. Nakai, and, S. Harada. 1997. Lack of infectivity of HIV-1 integrase zinc finger-like domain mutant with morphologically normal maturation. Biochem. Biophys. Res. Commun. 239:715722.
102. Nishizawa, Y.,, J. Usukura,, D. P. Singh,, L. T. Chylack, Jr., and, T. Shinohara. 2001. Spatial and temporal dynamics of two alternatively spliced regulatory factors, lens epithelium-derived growth factor (ledgf/p75) and p52, in the nucleus. Cell Tissue Res. 305:107114.
103. Pandey, K. K.,, S. Bera,, J. Zahm,, A. Vora,, K. Stillmock,, D. Hazuda, and, D. P. Grandgenett. 2007. Inhibition of human immunodeficiency virus type-1 concerted integration by strand transfer inhibitors which recognize a transient structural intermediate. J. Virol. 81:1218912199.
104. Pannecouque, C.,, W. Pluymers,, B. Van Maele,, V. Tetz,, P. Cherepanov,, E. De Clercq,, M. Witvrouw, and, Z. Debyser. 2002. New class of HIV integrase inhibitors that block viral replication in cell culture. Curr. Biol. 12:11691177.
105. Parissi, V.,, C. Calmels,, V. R. De Soultrait,, A. Caumont,, M. Fournier,, S. Chaignepain, and, S. Litvak. 2001. Functional interactions of human immunodeficiency virus type 1 integrase with human and yeast HSP60. J. Virol. 75:1134411353.
106. Qiu, C.,, K. Sawada,, X. Zhang, and, X. Cheng. 2002. The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nat. Struct. Biol. 9:217224.
107. Raghavendra, N. K., and, A. Engelman. 2007. LEDGF/p75 interferes with the formation of synaptic nucleoprotein complexes that catalyze full-site HIV-1 DNA integration in vitro: implications for the mechanism of viral cDNA integration. Virology 360:15.
108. Ramanathan, S.,, G. Shen,, J. Hinkle,, J. Enejosa, and, B. P. Kearney. 2007. Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase inhibitor GS-9137 (elvitegravir) and acid-reducing agents. 8th International Workshop in Clinical Pharmacology and HIV Therapy, Budapest, Hungary.
109. Ramanathan, S.,, G. Shen,, A. Cheng, and, B. P. Kearney. 2007. Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137. J. Acquir. Immune Defic. Syndr. 45:274279.
110. Ramanathan, S.,, W. Shen,, S. Abel,, J. Enejosa, and, B. P. Kearney. 2007. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir plus maraviroc. 47th Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL.
111. Ramanathan, S,, W. Shen,, T. N. Kakuda,, R. Mack,, C. Holmes, and, B. P. Kearney. 2007. Lack of clinically relevant drug interactions between ritonavir-boosted elvitegravir and TMC125. 47th Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL.
112. Rhame, F.,, M. Long, and, E. Acosta. 2008. RAL-KAL: pharmacokinetics of coadministered raltegravir and lopinavir-ritonavir in healthy adults, abstr. O19. 9th International Workshop on Clinical Pharmacology of HIV Therapy, New Orleans, LA, April 2008.
113. Ryan, D. P., and, J. M. Matthews. 2005. Protein-protein interactions in human disease. Curr. Opin. Struct. Biol. 15:441446.
114. Sandmeyer, S. 2003. Integration by design. Proc. Natl. Acad. Sci. USA 100:55865588.
115. Schroder, A. R.,, P. Shinn,, H. Chen,, C. Berry,, J. R. Ecker, and, F. Bushman. 2002. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110:521529.
116. Sharma, P.,, D. P. Singh,, N. Fatma,, L. T. Chylack, Jr., and, T. Shinohara. 2000. Activation of LEDGF gene by thermal-and oxidative-stresses. Biochem. Biophys. Res. Commun. 276:13201324.
117. Sheehy, A. M.,, N. C. Gaddis,, J. D. Choi, and, M. H. Malim. 2002. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418:646650.
118. Shinohara, T.,, D. P. Singh, and, N. Fatma. 2002. LEDGF, a survival factor, activates stress-related genes. Prog. Retin. Eye Res. 21:341358.
119. Shun, M. C.,, J. E. Daigle,, N. Vandegraaff, and, A. Engelman. 2007. Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein. J. Virol. 81:166172.
120. Shun, M. C.,, N. K. Raghavendra,, N. Vandegraaff,, J. E. Daigle,, S. Hughes,, P. Kellam,, P. Cherepanov, and, A. Engelman. 2007. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21:17671778.
121. Singh, D. P.,, N. Fatma,, A. Kimura,, L. T. Chylack, Jr., and, T. Shinohara. 2001. LEDGF binds to heat shock and stress-related element to activate the expression of stress-related genes. Biochem. Biophys. Res. Commun. 283:943955.
122. Singh, D. P.,, N. Ohguro,, T. Kikuchi,, T. Sueno,, V. N. Reddy,, K. Yuge,, L. T. Chylack, Jr.,, T. Shinohara,, N. Fatma, and, A. Kimura. 2000. Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts. Biochem. Biophys. Res. Commun. 267:373381.
123. Stec, I.,, S. B. Nagl,, G. J. van Ommen, and, J. T. den Dunnen. 2000. The PWWP domain: a potential protein-protein interaction domain in nuclear proteins influencing differentiation? FEBS Lett. 473:15.
124. Steigbigel, R. T.,, D. A. Cooper,, P. N. Kumar,, J. E. Eron,, M. Schechter,, M. Markowitz,, M. R. Loutfy,, J. L. Lennox,, J. M. Gatell,, J. K. Rockstroh,, C. Katlama,, P. Yeni,, A. Lazzarin,, B. Clotet,, J. Zhao,, J. Chen,, D. M. Ryan,, R. R. Rhodes,, J. A. Killar,, L. R. Gilde,, K. M. Strohmaier,, A. R. Meibohm,, M. D. Miller,, D. J. Hazuda,, M. L. Nessly,, M. J. DiNubile,, R. D. Isaacs,, B. Y. Nguyen,, H. Teppler, and BENCHMRK Study Teams. 2008. Raltegravir with optimized background therapy for resistant HIV-1 infection. New Engl. J. Med. 359:339354.
125. Stremlau, M.,, C. M. Owens,, M. J. Perron,, M. Kiessling,, P. Autissier, and, J. Sodroski. 2004. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 427:848853.
126. Sunila Reddy, S. M.,, J. Borland,, I. Song,, J. Lin,, A. Mehta,, S. Palleja, and, W. Symonds. 2007. A double-blind, parallel, randomized, placebo-controlled, single and repeat dose-escalation study to investigate the safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor GSK364735 in healthy subjects (GRZ105655). Conference on Retroviruses and Opportunistic Infections, 2007, Los Angeles, CA.
127. Suzuki, Y., and, R. Craigie. 2002. Regulatory mechanisms by which barrier-to-autointegration factor blocks autointegration and stimulates intermolecular integration of Moloney murine leukemia virus preintegration complexes. J. Virol. 76:1237612380.
128. Suzuki, Y.,, H. Yang, and, R. Craigie. 2004. LAP2alpha and BAF collaborate to organize the Moloney murine leukemia virus pre-integration complex. EMBO J. 23:46704678.
129. Teppler, H.,, N. Azrolan,, J. Chen,, B. Y. Nguyen, et al. 2006. Differential effects of MK-0518 and efavirenz on serum lipids and lipoproteins in antiretroviral therapy (ART)-naïve patients (24-week results), abstr. H-256a. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA.
130. Turlure, F.,, E. Devroe,, P. A. Silver, and, A. Engelman. 2004. Human cell proteins and human immunodeficiency virus DNA integration. Front. Biosci. 9:31873208.
131. van Aubel, R. A.,, P. H. Smeets,, J. G. Peters,, R. J. Bindels, and, F. G. Russel. 2002. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol. 13:595603.
132. Vandekerckhove, L.,, F. Christ,, B. Van Maele,, J. De Rijck,, R. Gijsbers,, C. Van den Haute,, M. Witvrouw, and, Z. Debyser. 2006. Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J. Virol. 80:18861896.
133. van den Ent, F. M.,, A. Vos, and, R. H. Plasterk. 1999. Dissecting the role of the N-terminal domain of human immunodeficiency virus integrase by trans-complementation analysis. J. Virol. 73:31763183.
134. Vanegas, M.,, M. Llano,, S. Delgado,, D. Thompson,, M. Peretz, and, E. Poeschla. 2005. Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLS-independent chromatin tethering. J. Cell Sci. 118:17331743.
135. Van Maele, B.,, K. Busschots,, L. Vandekerckhove,, F. Christ, and, Z. Debyser. 2006. Cellular co-factors of HIV-1 integration. Trends Biochem. Sci. 31:98105.
136. Van Maele, B.,, J. De Rijck,, E. De Clercq, and, Z. Debyser. 2003. Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction. J. Virol. 77:46854694.
137. Vassilev, L. T. 2004. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3:419421.
138. Violot, S.,, S. S. Hong,, D. Rakotobe,, C. Petit,, B. Gay,, K. Moreau,, G. Billaud,, S. Priet,, J. Sire,, O. Schwartz,, J. F. Mouscadet, and, P. Boulanger. 2003. The human polycomb group EED protein interacts with the integrase of human immunodeficiency virus type 1. J. Virol. 77:1250712522.
139. Wai, J.,, T. Fisher,, M. Embrey,, M. Egbertson,, J. Vacca,, D. Hazuda,, M. Miller,, M. Witmer,, L. Gabryelski, and, T. Lyle. 2007. Next generation of inhibitors of hiv-1 integrase strand transfer inhibitor: structural diversity and resistance profiles. Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA.
140. Wang, J. Y.,, H. Ling,, W. Yang, and, R. Craigie. 2001. Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein. EMBO J. 20:73337343.
141. Wang, W.,, J. Cote,, Y. Xue,, S. Zhou,, P. A. Khavari,, S. R. Biggar,, C. Muchardt,, G. V. Kalpana,, S. P. Goff,, M. Yaniv,, J. L. Workman, and, G. R. Crabtree. 1996. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15:53705382.
142. Wang, Z.,, B. Wang,, K. Tang,, E. J. Lee,, S. S. Chong, and, C. G. Lee. 2005. A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection. Hum. Mol. Genet. 14:20752087.
143. Wenning, L. A.,, E. Friedman, and, J. T. Kost. 2006. Lack of a significant drug interaction between MK-0518 and tenofovir disoproxil fumarate (TDF), abstr. A-375, p. 8. Abstr. 46th Inter-sci. Conf. Antimicrob. Agents Chemother., San Francisco, CA.
144. Wenning, L. A.,, H. Hanley, and, J Stone. 2006. Effect of tipranavir + ritonavir (TPV + RTV) on pharmacokinetics of MK-0518, abstr. A-374. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA.
145. Williams, G. C.,, A. Liu,, G. Knipp, and, P. J. Sinko. 2002. Direct evidence that saquinavir is transported by multidrug resistance-associated protein (MRP1) and canalicular multispecific organic anion transporter (MRP2). Antimicrob. Agents Chemother. 46:34563462.
146. Wu, X.,, T. Daniels,, C. Molinaro,, M. B. Lilly, and, C. A. Casiano. 2002. Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders. Cell Death Differ. 9:915925.
147. Wu, X.,, Y. Li,, B. Crise, and, S. M. Burgess. 2003. Transcription start regions in the human genome are favored targets for MLV integration. Science 300:17491751.
148. Yoder, K. E., and, F. D. Bushman. 2000. Repair of gaps in retroviral DNA integration intermediates. J. Virol. 74:1119111200.
149. Yuasa, I.,, K. Umetsu,, U. Vogt,, H. Nakamura,, E. Nanba,, N. Tamaki, and, Y. Irizawa. 1997. Human orosomucoid polymorphism: molecular basis of the three common ORM1 alleles, ORM1*F1, ORM1*F2, and ORM1*S. Hum. Genet. 99:393398.
150. Yung, E.,, M. Sorin,, A. Pal,, E. Craig,, A. Morozov,, O. Delattre,, J. Kappes,, D. Ott, and, G. V. Kalpana. 2001. Inhibition of HIV-1 virion production by a transdominant mutant of integrase inter-actor 1. Nat. Med. 7:920926.
151. Zheng, R.,, T. M. Jenkins, and, R. Craigie. 1996. Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity. Proc. Natl. Acad. Sci. USA 93:1365913664.
152. Zhuang, L.,, J. S. Wai,, M. W. Embrey,, T. E. Fisher,, M. S. Egbertson,, L. S. Payne,, J. P. Guare, Jr.,, J. P. Vacca,, D. J. Hazuda,, P. J. Felock,, A. L. Wolfe,, K. A. Stillmock,, M. V. Witmer,, G. Moyer,, W. A. Schleif,, L. J. Gabryelski,, Y. M. Leonard,, J. J. Lynch, Jr.,, S. R. Michelson, and, S. D. Young. 2003. Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J. Med. Chem. 46:453456.
153. Zielske, S. P., and, M. Stevenson. 2006. Modest but reproducible inhibition of human immunodeficiency virus type 1 infection in macrophages following LEDGFp75 silencing. J. Virol. 80:72757280.
154. Zolopa, A. R.,, M. Mullen,, D. Berger,, P. Ruane,, T. Hawkins,, L. Zhong,, S. Chuck,, J. Enejosa,, B. Kearney, and, A. Cheng. 2007. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA.
155. Zouhiri, F.,, J. F. Mouscadet,, K. Mekouar,, D. Desmaele,, D. Savoure,, H. Leh,, F. Subra,, M. Le Bret,, C. Auclair, and, J. d’Angelo. 2000. Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture. J. Med. Chem. 43:15331540.

Tables

Generic image for table
Table 1.

Disposition characteristics and pharmacokinetic parameters of raltegravir and elvitegravir

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Generic image for table
Table 2.

Data from drug-drug interaction studies performed to date

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5
Generic image for table
Table 3.

Comparison of mutant and wild-type HIV-1 susceptibility to IN inhibitors

Citation: Vandekerckhove L, Christ F, Debyser Z, Owen A, Back D, Voet A, Schapiro J, Vogelaers D. 2009. Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives, p 71-96. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch5

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error