2. Academic Validation
  3. CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies

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

  • J Virol. 2014 Jun;88(12):6542-55. doi: 10.1128/JVI.00540-14.
Navid Madani 1,  Amy M Princiotto 2,  Arne Schön 3,  Judith LaLonde 4,  Yu Feng 5,  Ernesto Freire 3,  Jongwoo Park 6,  Joel R Courter 6,  David M Jones 6,  James Robinson 7,  Hua-Xin Liao 8,  M Anthony Moody 8,  Sallie Permar 8,  Barton Haynes 8,  Amos B Smith 3rd 6,  Richard Wyatt 5,  Joseph Sodroski 9
Affiliations

Affiliations

  • 1 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 3 Department of Biology, The Johns Hopkins University, Baltimore, Maryland, USA.
  • 4 Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania, USA.
  • 5 IAVI Neutralizing Antibody Center at TSRI, The Scripps Research Institute, La Jolla, California, USA.
  • 6 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 7 Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana, USA.
  • 8 Duke Human Vaccine Institute, Department of Medicine, Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
  • 9 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA joseph_sodroski@dfci.harvard.edu.
PMID: 24696475 DOI: 10.1128/JVI.00540-14
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.

Importance: Preventing HIV-1 transmission is a priority for global health. Eliciting Antibodies that can neutralize many different strains of HIV-1 is difficult, creating problems for the development of a vaccine. We found that certain small-molecule compounds can sensitize HIV-1 to particular Antibodies. These Antibodies can be elicited in rabbits. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-121820
    HIV-1 Inhibitor
    HIV