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Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study


Autoři: Ira Dicker aff001;  Sharon Zhang aff001;  Neelanjana Ray aff002;  Brett R. Beno aff003;  Alicia Regueiro-Ren aff004;  Samit Joshi aff005;  Mark Cockett aff001;  Mark Krystal aff001;  Max Lataillade aff005
Působiště autorů: Department of HIV Discovery, ViiV Healthcare, Branford, Connecticut, United States of America aff001;  Department of Early Development, Bristol-Myers Squibb Research and Development, Princeton, New Jersey, United States of America aff002;  Department of Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, United States of America aff003;  Department of Chemistry Bristol-Myers Squibb Research and Development, Wallingford Connecticut, United States of America aff004;  Department of Early Development, ViiV Healthcare, Branford, Connecticut, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0224076

Souhrn

GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants.

Klíčová slova:

HIV-1 – Viral replication – Proteases – Substitution mutation – Monomers – Viral packaging – Amino acid substitution


Zdroje

1. Bryant M, Ratner L. Myristoylation-dependent replication and assembly of human immunodeficiency virus 1. Proc Natl Acad Sci U S A. 1990;87(2):523–7. doi: 10.1073/pnas.87.2.523 2405382

2. Accola MA, Hoglund S, Gottlinger HG. A putative alpha-helical structure which overlaps the capsid-p2 boundary in the human immunodeficiency virus type 1 Gag precursor is crucial for viral particle assembly. J Virol. 1998;72(3):2072–8. 9499062

3. Pettit SC, Henderson GJ, Schiffer CA, Swanstrom R. Replacement of the P1 amino acid of human immunodeficiency virus type 1 Gag processing sites can inhibit or enhance the rate of cleavage by the viral protease. J Virol. 2002;76(20):10226–33. doi: 10.1128/JVI.76.20.10226-10233.2002 12239298

4. Wiegers K, Rutter G, Kottler H, Tessmer U, Hohenberg H, Krausslich HG. Sequential steps in human immunodeficiency virus particle maturation revealed by alterations of individual Gag polyprotein cleavage sites. J Virol. 1998;72(4):2846–54. 9525604

5. Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, et al. Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection. Antimicrob Agents Chemother. 2007;51(10):3574–81. doi: 10.1128/AAC.00152-07 17638699

6. Fun A, van Maarseveen NM, Pokorna J, Maas RE, Schipper PJ, Konvalinka J, et al. HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat. Retrovirology. 2011;8:70. Epub 2011/08/26. doi: 10.1186/1742-4690-8-70 21864346

7. Martin DE, Salzwedel K, Allaway GP. Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection. Antivir Chem Chemother. 2008;19(3):107–13. Epub 2008/11/26. doi: 10.1177/095632020801900301 19024627

8. Knapp DJ, Harrigan PR, Poon AF, Brumme ZL, Brockman M, Cheung PK. In vitro selection of clinically relevant bevirimat resistance mutations revealed by "deep" sequencing of serially passaged, quasispecies-containing recombinant HIV-1. J Clin Microbiol. 2011;49(1):201–8. Epub 2010/11/19. doi: 10.1128/JCM.01868-10 21084518

9. Van Baelen K, Salzwedel K, Rondelez E, Van Eygen V, De Vos S, Verheyen A, et al. Susceptibility of human immunodeficiency virus type 1 to the maturation inhibitor bevirimat is modulated by baseline polymorphisms in Gag spacer peptide 1. Antimicrob Agents Chemother. 2009;53(5):2185–8. doi: 10.1128/AAC.01650-08 19223634

10. Adamson CS, Sakalian M, Salzwedel K, Freed EO. Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1 maturation inhibitor bevirimat. Retrovirology. 2010;7:36. Epub 2010/04/22. doi: 10.1186/1742-4690-7-36 20406463

11. Los Alamos National Laboratory. HIV databases. 2018: http://www.hiv.lanl.gov/.

12. Margot NA, Gibbs CS, Miller MD. Phenotypic susceptibility to bevirimat in isolates from HIV-1-infected patients without prior exposure to bevirimat. Antimicrob Agents Chemother. 2010;54(6):2345–53. doi: 10.1128/AAC.01784-09 20308382

13. Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, et al. New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation. Antimicrob Agents Chemother. 2009;53(12):5080–7. doi: 10.1128/AAC.00759-09 19805571

14. Waki K, Durell SR, Soheilian F, Nagashima K, Butler SL, Freed EO. Structural and functional insights into the HIV-1 maturation inhibitor binding pocket. PLoS Pathog. 2012;8(11):e1002997. Epub 2012/11/13. doi: 10.1371/journal.ppat.1002997 23144615

15. Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Sun Y, et al. Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage. Antimicrob Agents Chemother. 2016;60(7):3956–69. doi: 10.1128/AAC.02560-15 27090171

16. Lin Z, Cantone J, Lu H, Nowicka-Sans B, Protack T, Yuan T, et al. Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors. PLoS Pathog. 2016;12(11):e1005990. doi: 10.1371/journal.ppat.1005990 27893830

17. Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, et al. Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity. ACS Med Chem Lett. 2016;7(6):568–72. doi: 10.1021/acsmedchemlett.6b00010 27326328

18. Regueiro-Ren A, Dicker IB, Hanumegowda U, Meanwell NA. Second Generation Inhibitors of HIV-1 Maturation. ACS Med Chem Lett. 2019;10(3):287–94. Epub 2019/03/21. doi: 10.1021/acsmedchemlett.8b00656 30891128

19. Morales-Ramirez J, Bogner JR, Molina JM, Lombaard J, Dicker IB, Stock DA, et al. Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial. PLoS One. 2018;13(10):e0205368. Epub 2018/10/24. doi: 10.1371/journal.pone.0205368 30352054

20. Hwang C, Schurmann D, Sobotha C, Boffito M, Sevinsky H, Ray N, et al. Antiviral Activity, Safety, and Exposure-Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002). Clin Infect Dis. 2017;65(3):442–52. doi: 10.1093/cid/cix239 28369211

21. Schur FK, Obr M, Hagen WJ, Wan W, Jakobi AJ, Kirkpatrick JM, et al. An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation. Science. 2016;353(6298):506–8. doi: 10.1126/science.aaf9620 27417497

22. Schrödinger Release 2018–3. Maestro. Schrödinger, LLC, New York, NY 2018.

23. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27(3):221–34. doi: 10.1007/s10822-013-9644-8 23579614

24. Schrödinger Release 2018–3. Schrödinger Suite 2018–3, Protein Preparation Wizard; Epik. Schrödinger, LLC, New York, NY, 2016; Impact, Schrödinger, LLC, New York, NY, 2016; Prime, Schrödinger, LLC, New York, NY. 2018.

25. Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, et al. OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. J Chem Theory Comput. 2016;12(1):281–96. doi: 10.1021/acs.jctc.5b00864 26584231

26. Schrödinger Release 2018–3. MacroModel. Schrödinger, LLC, New York, NY, 2018. 2018.

27. Purdy MD, Shi D, Chrustowicz J, Hattne J, Gonen T, Yeager M. MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat. Proceedings of the National Academy of Sciences. 2018:13258–1326.

28. Schrödinger Release 2018–3. Desmond Molecular Dynamics System, D.E. Shaw Research, New York, NY, 2018. Maestro-Desmond Interoperablity Tools, Schrödinger, New York, NY. 2018.

29. Schrödinger Release 2018–3. Maestro-Desmond Interoperability Tools. 2018.

30. Ray N, Li T, Lin Z, Protack T, van Ham PM, Hwang C, et al. The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor-Resistant Clinical Isolates. J Acquir Immune Defic Syndr. 2017;75(1):52–60. doi: 10.1097/QAI.0000000000001304 28234686

31. Choe S, Feng Y, Kimoli KL, editors. Measurement of maturation inhibitor susceptibility using the PhenSense HV Assay. 15th Conference on Retroviruses and Opportunistic Infections; 2008 February 2–8; Boston, MA.

32. Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, et al. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2000;44(4):920–8. doi: 10.1128/aac.44.4.920-928.2000 10722492

33. Parry CM, Kohli A, Boinett CJ, Towers GJ, McCormick AL, Pillay D. Gag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1. J Virol. 2009;83(18):9094–101. doi: 10.1128/JVI.02356-08 19587031

34. Adamson CS, Ablan SD, Boeras I, Goila-Gaur R, Soheilian F, Nagashima K, et al. In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J Virol. 2006;80(22):10957–71. doi: 10.1128/JVI.01369-06 16956950

35. Prabu-Jeyabalan M, Nalivaika E, Schiffer CA. Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes. Structure. 2002;10(3):369–81. doi: 10.1016/s0969-2126(02)00720-7 12005435

36. Wagner JM, Zadrozny KK, Chrustowicz J, Purdy MD, Yeager M, Ganser-Pornillos BK, et al. Crystal structure of an HIV assembly and maturation switch. Elife. 2016;5.

37. Keller PW, Adamson CS, Heymann JB, Freed EO, Steven AC. HIV-1 maturation inhibitor bevirimat stabilizes the immature Gag lattice. J Virol. 2011;85(4):1420–8. Epub 2010/11/26. doi: 10.1128/JVI.01926-10 21106735

38. Urano E, Timilsina U, Kaplan JA, Ablan S, Ghimire D, Pham P, et al. Resistance to Second-Generation HIV-1 Maturation Inhibitors. J Virol. 2019;93(6). Epub 2018/12/21.

39. Knapp D, Huang S, Harrigan R, editors. Stable prevalence of bevirimat-related HIV Gag polymorphisms both before and after HAART exposure. 16th Conference on Retroviruses and Opportunistic Infections; 2009; Montreal, CA.

40. Votteler J, Wray V, Shubert U. Role of cyclophilin A in HIV replication. Future Virology. 2007;2(1):65–78.

41. Sokolskaja E, Sayah DM, Luban J. Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity. J Virol. 2004;78(23):12800–8. doi: 10.1128/JVI.78.23.12800-12808.2004 15542632

42. Gatanaga H, Das D, Suzuki Y, Yeh DD, Hussain KA, Ghosh AK, 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. J Biol Chem. 2006;281(2):1241–50. doi: 10.1074/jbc.M505920200 16275650

43. Yin L, Braaten D, Luban J. Human immunodeficiency virus type 1 replication is modulated by host cyclophilin A expression levels. J Virol. 1998;72(8):6430–6. 9658084

44. Wensing AM, Calvez V, Gunthard HF, Johnson VA, Paredes R, Pillay D, et al. 2017 Update of the Drug Resistance Mutations in HIV-1. Top Antivir Med. 2017;24(4):132–3. 28208121

45. Dierynck I, Van Marck H, Van Ginderen M, Jonckers TH, Nalam MN, Schiffer CA, et al. TMC310911, a novel human immunodeficiency virus type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors. Antimicrob Agents Chemother. 2011;55(12):5723–31. doi: 10.1128/AAC.00748-11 21896904

46. Stray KM, Callebaut C, Glass B, Tsai L, Xu L, Muller B, et al. Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374. J Virol. 2013;87(1):454–63. doi: 10.1128/JVI.01211-12 23097440


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