Residues in the gp41 ectodomain regulate HIV-1 envelope glycoprotein conformational transitions induced by gp120-directed inhibitors

Beatriz Pacheco, Nirmin Alsahafi, Olfa Debbeche, Jérémie Prévost, Shilei Ding, Jean Philippe Chapleau, Alon Herschhorn, Navid Madani, Amy Princiotto, Bruno Melillo, Christopher Gu, Xin Zeng, Youdong Mao, Amos B. Smith, Joseph Sodroski, Andrés Finzia

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations.

Original languageEnglish (US)
Article numbere02219-16
JournalJournal of virology
Volume91
Issue number5
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We thank Yvette McLaughlin, Elizabeth Carpelan, and Julia Barnes for manuscript preparation. This work was supported by grants from the National Institutes of Health (AI24755, AI24982, GM56550, and AI67854), by the International AIDS Vaccine Initiative, by a grant from the late William F. McCarty-Cooper to J.S., by Canada Foundation for Innovation Program Leader grant 29866, and by CIHR Foundation grant 352417 to A.F. A.F. was supported by phases I and II of the amfAR Mathilde Krim Fellowship in Basic Biomedical Research (107963-49-RKVA). A.F. is the recipient of a Canada Research Chair on Retroviral Entry (grant 950-229930). N.A. is the recipient of a King Abdullah scholarship for higher education from the Saudi Government. N.M. was supported by amfAR grant 107431-45-RFNT, NIH grant AI090682, and a Ragon Institute Innovation Award. A.H. is the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (108501-53-RKNT) and was also supported by a phase II amfAR research grant (109285-58-RKVA) for independent investigators. We have no conflicts of interest to report.

Publisher Copyright:
© 2017 American Society for Microbiology.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • Antibody resistance
  • Gp120
  • Gp41
  • HIV-1
  • HR1
  • Intrinsic envelope reactivity
  • Soluble CD4

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