Long-Acting bms-378806 analogues stabilize the state-1 conformation of the human immunodeficiency virus type 1 envelope glycoproteins

Shitao Zou, Shijian Zhang, Althea Gaffney, Haitao Ding, Maolin Lu, Jonathan R. Grover, Mark Farrell, Hanh T. Nguyen, Connie Zhao, Saumya Anang, Meiqing Zhao, Mohammadjavad Mohammadi, Scott C. Blanchard, Cameron Abrams, Navid Madani, Walther Mothes, John C. Kappes, Amos B. Smith, Joseph Sodroski

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

During human immunodeficiency virus type 1 (HIV-1) entry into cells, the viral envelope glycoprotein (Env) trimer [(gp120/gp41)3] binds the receptors CD4 and CCR5 and fuses the viral and cell membranes. CD4 binding changes Env from a pretriggered (state-1) conformation to more open downstream conformations. BMS-378806 (here called BMS-806) blocks CD4-induced conformational changes in Env important for entry and is hypothesized to stabilize a state-1-like Env conformation, a key vaccine target. Here, we evaluated the effects of BMS-806 on the conformation of Env on the surface of cells and virus-like particles. BMS-806 strengthened the labile, noncovalent interaction of gp120 with the Env trimer, enhanced or maintained the binding of most broadly neutralizing antibodies, and decreased the binding of poorly neutralizing antibodies. Thus, in the presence of BMS-806, the cleaved Env on the surface of cells and virus-like particles exhibits an antigenic profile consistent with a state-1 conformation. We designed novel BMS-806 analogues that stabilized the Env conformation for several weeks after a single application. These long-Acting BMS-806 analogues may facilitate enrichment of the metastable state-1 Env conformation for structural characterization and presentation to the immune system.

Original languageEnglish
Article numbere00148-20
JournalJournal of Virology
Volume94
Issue number10
DOIs
StatePublished - 1 May 2020
Externally publishedYes

Keywords

  • Entry inhibitor
  • Envelope
  • Immunogen
  • Lentivirus
  • Retrovirus
  • Structure
  • Vaccine
  • Virus

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