CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies

Navid Madani, Amy M. Princiotto, Arne Schön, Judith LaLonde, Yu Feng, Ernesto Freire, Jongwoo Park, Joel R. Courter, David M. Jones, James Robinson, Hua Xin Liao, Anthony A. Moody, Sallie Permar, Barton Haynes, Amos B. Smith, Richard Wyatt, Joseph Sodroski

Research output: Contribution to journalArticlepeer-review

Abstract

Approaches to prevent human immunodeficiency virus (HIV-1) transmission are urgently needed. Difficulties in eliciting antibodies that bind conserved epitopes exposed on the unliganded conformation of the HIV-1 envelope glycoprotein (Env) trimer represent barriers to vaccine development. During HIV-1 entry, binding of the gp120 Env to the initial receptor, CD4, triggers conformational changes in Env that result in the formation and exposure of the highly conserved gp120 site for interaction with the coreceptors, CCR5 and CXCR4. The DMJ compounds (+)-DMJ-I-228 and (+)-DMJ-II-121 bind gp120 within the conserved Phe 43 cavity near the CD4-binding site, block CD4 binding, and inhibit HIV-1 infection. Here we show that the DMJ compounds sensitize primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies directed against CD4-induced (CD4i) epitopes and the V3 region, two gp120 elements involved in coreceptor binding. Importantly, the DMJ compounds rendered primary HIV-1 sensitive to neutralization by antisera elicited by immunization of rabbits with HIV-1 gp120 cores engineered to assume the CD4-bound state. Thus, small molecules like the DMJ compounds may be useful as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies.

Original languageEnglish (US)
Pages (from-to)6542-6555
Number of pages14
JournalJournal of virology
Volume88
Issue number12
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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