title: Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds.
abstract: The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.
  
  
  
  Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Princiotto
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Easterhoff
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Bradley
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Luo
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Wilton B
authors.initials: WB
authors.lastname: Williams
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ganesh E
authors.initials: GE
authors.lastname: Phad
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Néstor
authors.initials: N
authors.lastname: Vázquez Bernat
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Melillo
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sampa
authors.initials: S
authors.lastname: Santra
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
authors.affiliation: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Barton
authors.initials: B
authors.lastname: Haynes
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA joseph_sodroski@dfci.harvard.edu.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.|Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000302:isolation & purification; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D000882:Haplorhini; D006801:Humans; D007114:Immunization; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D054299:env Gene Products, Human Immunodeficiency Virus