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

Alon Herschhorn, Christopher Gu, Nicole Espy, Jonathan Richard, Andrés Finzi, Joseph G. Sodroski

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)845-852
Number of pages8
JournalNature Chemical Biology
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2014

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2014 Nature America, Inc. All rights reserved.

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