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Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds.

Publication ,  Journal Article
Madani, N; Princiotto, AM; Easterhoff, D; Bradley, T; Luo, K; Williams, WB; Liao, H-X; Moody, MA; Phad, GE; Vázquez Bernat, N; Melillo, B ...
Published in: J Virol
May 15, 2016

UNLABELLED: 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. IMPORTANCE: 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.

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Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

May 15, 2016

Volume

90

Issue

10

Start / End Page

5031 / 5046

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Peptide Fragments
  • Molecular Mimicry
  • Immunization
  • Humans
  • Haplorhini
  • HIV-1
  • HIV Infections
  • HIV Envelope Protein gp120
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Madani, N., Princiotto, A. M., Easterhoff, D., Bradley, T., Luo, K., Williams, W. B., … Sodroski, J. (2016). Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds. J Virol, 90(10), 5031–5046. https://doi.org/10.1128/JVI.03211-15
Madani, Navid, Amy M. Princiotto, David Easterhoff, Todd Bradley, Kan Luo, Wilton B. Williams, Hua-Xin Liao, et al. “Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds.J Virol 90, no. 10 (May 15, 2016): 5031–46. https://doi.org/10.1128/JVI.03211-15.
Madani N, Princiotto AM, Easterhoff D, Bradley T, Luo K, Williams WB, et al. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds. J Virol. 2016 May 15;90(10):5031–46.
Madani N, Princiotto AM, Easterhoff D, Bradley T, Luo K, Williams WB, Liao H-X, Moody MA, Phad GE, Vázquez Bernat N, Melillo B, Santra S, Smith AB, Karlsson Hedestam GB, Haynes B, Sodroski J. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds. J Virol. 2016 May 15;90(10):5031–5046.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

May 15, 2016

Volume

90

Issue

10

Start / End Page

5031 / 5046

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Peptide Fragments
  • Molecular Mimicry
  • Immunization
  • Humans
  • Haplorhini
  • HIV-1
  • HIV Infections
  • HIV Envelope Protein gp120