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A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry

Nature Chemical Biology volume 10, pages 845–852 (2014)Cite this article

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Abstract

Binding to the primary receptor, CD4, triggers conformational changes in the metastable HIV-1 envelope glycoprotein (Env) trimer ((gp120-gp41)3) that are important for virus entry into host cells. These changes include an 'opening' of the trimer, creation of a binding site for the CCR5 co-receptor and formation and/or exposure of a gp41 coiled coil. Here we identify a new compound, 18A (1), that specifically inhibits the entry of a wide range of HIV-1 isolates. 18A does not interfere with CD4 or CCR5 binding, but it inhibits the CD4-induced disruption of quaternary structures at the trimer apex and the exposure of the gp41 HR1 coiled coil. Analysis of HIV-1 variants with increased or reduced sensitivity to 18A suggests that the inhibitor can distinguish distinct conformational states of gp120 in the unliganded Env trimer. The broad-range activity and observed hypersensitivity of resistant mutants to antibody neutralization support further investigation of 18A.

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Figure 1: Screening assay and data analysis.
Figure 2: Effects of 18A on infection of R5- and X4-tropic viruses.
Figure 3: Investigation of the target of 18A inhibition.
Figure 4: Effect of gp120 changes on HIV-1 sensitivity to 18A.
Figure 5: Mechanism of 18A inhibition of HIV-1 infection.
Figure 6: Model for the inhibition of HIV-1 entry by 18A.

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References

  1. Barré-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).

    Article  PubMed  Google Scholar 

  2. Gallo, R.C. et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224, 500–503 (1984).

    Article  CAS  PubMed  Google Scholar 

  3. Choe, H. et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135–1148 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Dalgleish, A.G. et al. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312, 763–767 (1984).

    Article  CAS  PubMed  Google Scholar 

  5. Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC–CKR-5. Nature 381, 667–673 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Feng, Y., Broder, C.C., Kennedy, P.E. & Berger, E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein–coupled receptor. Science 272, 872–877 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Furuta, R.A., Wild, C.T., Weng, Y. & Weiss, C.D. Capture of an early fusion-active conformation of HIV-1 gp41. Nat. Struct. Biol. 5, 276–279 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. He, Y. et al. Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites. J. Virol. 77, 1666–1671 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Koshiba, T. & Chan, D.C. The prefusogenic intermediate of HIV-1 gp41 contains exposed C-peptide regions. J. Biol. Chem. 278, 7573–7579 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Kwon, Y.D. et al. Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc. Natl. Acad. Sci. USA 109, 5663–5668 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Madani, N. et al. Small-molecule CD4 mimics interact with a highly conserved pocket on HIV-1 gp120. Structure 16, 1689–1701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin, P.F. et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc. Natl. Acad. Sci. USA 100, 11013–11018 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Si, Z. et al. Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc. Natl. Acad. Sci. USA 101, 5036–5041 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. LaLonde, J.M. et al. Structure-based design, synthesis, and characterization of dual hotspot small-molecule HIV-1 entry inhibitors. J. Med. Chem. 55, 4382–4396 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Regueiro-Ren, A. et al. Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 12. Structure-activity relationships associated with 4-fluoro-6-azaindole derivatives leading to the identification of 1-(4-benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1h-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248). J. Med. Chem. 56, 1656–1669 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Schader, S.M. et al. HIV gp120 H375 is unique to HIV-1 subtype CRF01_AE and confers strong resistance to the entry inhibitor BMS-599793, a candidate microbicide drug. Antimicrob. Agents Chemother. 56, 4257–4267 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Keele, B.F. et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl. Acad. Sci. USA 105, 7552–7557 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kolchinsky, P., Kiprilov, E., Bartley, P., Rubinstein, R. & Sodroski, J. Loss of a single N-linked glycan allows CD4-independent human immunodeficiency virus type 1 infection by altering the position of the gp120 V1/V2 variable loops. J. Virol. 75, 3435–3443 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Julien, J.P. et al. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog. 9, e1003342 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wyatt, R. et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393, 705–711 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Xiang, S.H. et al. Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains. Virology 315, 124–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Zhou, T. et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811–817 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rizzuto, C.D. et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280, 1949–1953 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Julien, J.P. et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 1477–1483 (2013).

  25. Haim, H. et al. Contribution of intrinsic reactivity of the HIV-1 envelope glycoproteins to CD4-independent infection and global inhibitor sensitivity. PLoS Pathog. 7, e1002101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McGee, K. et al. The selection of low envelope glycoprotein reactivity to soluble CD4 and cold during simian-human immunodeficiency virus infection of rhesus macaques. J. Virol. 88, 21–40 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Scott, C.F. Jr. et al. Human monoclonal antibody that recognizes the V3 region of human immunodeficiency virus gp120 and neutralizes the human T-lymphotropic virus type IIIMN strain. Proc. Natl. Acad. Sci. USA 87, 8597–8601 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Haim, H. et al. Modeling virus- and antibody-specific factors to predict human immunodeficiency virus neutralization efficiency. Cell Host Microbe 14, 547–558 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Kassa, A. et al. Identification of a human immunodeficiency virus type 1 envelope glycoprotein variant resistant to cold inactivation. J. Virol. 83, 4476–4488 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kassa, A. et al. Transitions to and from the CD4-bound conformation are modulated by a single-residue change in the human immunodeficiency virus type 1 gp120 inner domain. J. Virol. 83, 8364–8378 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Doores, K.J. & Burton, D.R. Variable loop glycan dependency of the broad and potent HIV-1-neutralizing antibodies PG9 and PG16. J. Virol. 84, 10510–10521 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Walker, L.M. et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McLellan, J.S. et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336–343 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Julien, J.P. et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc. Natl. Acad. Sci. USA 110, 4351–4356 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Walker, L.M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, J., Bartesaghi, A., Borgnia, M.J., Sapiro, G. & Subramaniam, S. Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Decker, J.M. et al. Antigenic conservation and immunogenicity of the HIV coreceptor binding site. J. Exp. Med. 201, 1407–1419 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Herschhorn, A. et al. An inducible cell-cell fusion system with integrated ability to measure the efficiency and specificity of HIV-1 entry inhibitors. PLoS ONE 6, e26731 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pettersen, E.F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Herschhorn, A. & Hizi, A. Virtual screening, identification, and biochemical characterization of novel inhibitors of the reverse transcriptase of human immunodeficiency virus type-1. J. Med. Chem. 51, 5702–5713 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Y. McLaughlin and E. Carpelan for manuscript preparation; the AIDS Research and the Reference Reagent Program, Division of AIDS, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH) for providing reference panels for subtype B and C HIV-1 envelope clones, CFR01_AE.269 HIV-1 envelope clone, psPAX2 plasmid, T20, maraviroc and CEM cells. We also thank B. Keele, G.M. Shaw and the Center for HIV-AIDS Vaccine Immunology Consortium for providing transmitted/founder HIV-1 envelope clones; H.-X. Liao and B.F. Haynes (Duke University Medical Center) for providing the CRF01_AE.CM244 HIV-1 envelope clone; D. Burton (The Scripps Research Institute), J. Robinson (Tulane University) and P.D. Kwong (Vaccine Research Center, NIH) for providing the anti-gp120 monoclonal antibodies; D. Flood, J. Smith and C. Shamu (Institute of Chemistry and Cell Biology, Harvard Medical School) for assistance in the high-throughput screening campaign; and E. Pery, E. Cassol, V. Misra, N. Madani, H. Haim and A.M. Princiotto from Dana-Farber Cancer Institute for helpful discussions and for providing reagents. A.H. was supported by amfAR and is the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (108501-53-RKNT). A.F. was supported by Canadian Institutes of Health Research operating grant number 119334 and is the recipient of a Fonds de la recherche en santé du Québec Chercheur Boursier Junior fellowship number 24639 and a Canada Research Chair on Retroviral Entry. Support for this work was also provided by grants from the NIH to J.G.S. (grant numbers AI24755 and GM56550).

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Authors and Affiliations

  1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Alon Herschhorn, Christopher Gu, Nicole Espy & Joseph G Sodroski

  2. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA

    Alon Herschhorn, Nicole Espy & Joseph G Sodroski

  3. Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montreal, Quebec, Canada

    Jonathan Richard & Andrés Finzi

  4. Department of Microbiology, Infectiology and Immunology ,Université de Montréal, Montreal, Quebec, Canada

    Jonathan Richard & Andrés Finzi

  5. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

    Andrés Finzi

  6. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Joseph G Sodroski

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  1. Alon Herschhorn
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Contributions

A.H. and J.G.S. conceived and designed the experiments; A.H. and C.G. performed the screening, viral and cell-cell fusion inhibition assays, chimera and mutant Env engineering and antibody binding and inhibition experiments; N.E. performed some of the viability assays; J.R. and A.F. performed some of the Env mutagenesis and experiments assessing CD4-induced conformational changes; and A.H., A.F. and J.G.S. analyzed data and wrote the paper.

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Correspondence to Joseph G Sodroski.

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Supplementary Results, Supplementary Tables 1–5 and Supplementary Figures 1–15. (PDF 6450 kb)

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Herschhorn, A., Gu, C., Espy, N. et al. A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry. Nat Chem Biol 10, 845–852 (2014). https://doi.org/10.1038/nchembio.1623

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