Activation and inactivation of primary human immunodeficiency virus envelope glycoprotein trimers by CD4-mimetic compounds

Navid Madani, Amy M. Princiotto, Connie Zhao, Fatemeh Jahanbakhshsefidi, Max Mertens, Alon Herschhorn, Bruno Melillo, Amos B. Smith, Joseph Sodroski

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4- mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4- positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility.

Original languageEnglish (US)
Article numbere01880-16
JournalJournal of virology
Volume91
Issue number3
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We thank Elizabeth Carpelan for manuscript preparation. We thank Irwin Chaiken and Wayne Hendrickson for valuable discussions and input. This study was supported by the National Institutes of Health (GM56550 and AI24755) and the late William F. McCarty-Cooper. N.M. was supported by amfAR grant 107431-45-RFNT, NIH grant AI90682, and a Ragon Institute Innovation Award. A.H. was supported by amfAR research grant 109285-58-RKVA.

Keywords

  • Antibody
  • Conformation
  • Envelope glycoprotein
  • Inhibitor
  • Neutralization
  • Sensitization
  • Stoichiometry
  • Virus entry

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