Strain-dependent activation and inhibition of human immunodeficiency virus entry by a specific PF-68742 stereoisomer

Connie Zhao, Amy M. Princiotto, Hanh T. Nguyen, Shitao Zou, Meiqing Lily Zhao, Shijian Zhang, Alon Herschhorn, Mark Farrell, Karanbir Pahil, Bruno Melillo, Somisetti V. Sambasivarao, Cameron Abrams, Amos B. Smith, Navid Madani, Joseph Sodroski

Research output: Contribution to journalArticlepeer-review

Abstract

Human immunodeficiency virus (HIV-1) entry into cells is mediated by the viral envelope glycoprotein (Env) trimer, which consists of three gp120 exterior glycoproteins and three gp41 transmembrane glycoproteins. When gp120 binds sequentially to the receptors CD4 and CCR5 on the target cell, the metastable Env trimer is triggered to undergo entry-related conformational changes. PF-68742 is a small molecule that inhibits the infection of a subset of HIV-1 strains by interfering with an Env function other than receptor binding. Determinants of HIV-1 resistance to PF-68742 map to the disulfide loop and fusion peptide of gp41. Of the four possible PF-68742 stereoisomers, only one, MF275, inhibited the infection of CD4-positive CCR5-positive cells by some HIV-1 strains. MF275 inhibition of these HIV-1 strains occurred after CD4 binding but before the formation of the gp41 six-helix bundle. Unexpectedly, MF275 activated the infection of CD4-negative CCR5-positive cells by several HIV-1 strains resistant to the inhibitory effects of the compound in CD4-positive target cells. In contrast to CD4 complementation by CD4-mimetic compounds, activation of CD4-independent infection by MF275 did not depend upon the availability of the gp120 Phe 43 cavity. Sensitivity to inhibitors indicates that MF275-activated virus entry requires formation/exposure of the gp41 heptad repeat (HR1) as well as CCR5 binding. MF275 apparently activates a virus entry pathway parallel to that triggered by CD4 and CD4-mimetic compounds. Strain-dependent divergence in Env conformational transitions allows different outcomes, inhibition or activation, in response to MF275. Understanding the mechanisms of MF275 activity should assist efforts to optimize its utility. IMPORTANCE Envelope glycoprotein (Env) spikes on the surface of human immunodeficiency virus (HIV-1) bind target cell receptors, triggering changes in the shape of Env. We studied a small molecule, MF275, that also induced shape changes in Env. The consequences of MF275 interaction with Env depended on the HIV-1 strain, with infection by some viruses inhibited and infection by other viruses enhanced. These studies reveal the strain-dependent diversity of HIV-1 Envs as they undergo shape changes in proceeding down the entry pathway. Appreciation of this diversity will assist attempts to develop broadly active inhibitors of HIV-1 entry.

Original languageEnglish (US)
Article numbere01197-19
JournalJournal of virology
Volume93
Issue number21
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health (GM56550/AI150471 and AI24755) and the late William F. McCarty-Cooper. N.M. was supported by amfAR grant 107431-45-RFNT, NIH AI90682, and a Ragon Institute Innovation Award. A.H. was supported by the phase II amfAR research grant 109285-58-RKVA.

Funding Information:
We thank Elizabeth Carpelan for manuscript preparation. We also thank Irwin Chaiken and Wayne Hendrickson for valuable discussions and input. This study was supported by the National Institutes of Health (GM56550/AI150471 and AI24755) and the late William F. McCarty-Cooper. N.M. was supported by amfAR grant 107431-45-RFNT, NIH AI90682, and a Ragon Institute Innovation Award. A.H. was supported by the phase II amfAR research grant 109285-58-RKVA.

Publisher Copyright:
© 2019 American Society for Microbiology. All Rights Reserved.

Keywords

  • Antibody
  • CD4 independent
  • Conformational change
  • Env
  • Inhibitor
  • Mutant
  • Retrovirus
  • Sensitization
  • Variation

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