A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge

Navid Madani (), Amy M. Princiotto, Linh Mach, Shilei Ding, Jérémie Prevost, Jonathan Richard, Bhavna Hora, Laura Sutherland, Connie A. Zhao, Brandon P. Conn, Todd Bradley, M. Anthony Moody, Bruno Melillo, Andrés Finzi, Barton F. Haynes, Amos B. Smith (), Sampa Santra and Joseph Sodroski ()
Additional contact information
Navid Madani: Dana-Farber Cancer Institute
Amy M. Princiotto: Dana-Farber Cancer Institute
Linh Mach: Harvard Medical School
Shilei Ding: Centre de Recherche du CHUM
Jérémie Prevost: Centre de Recherche du CHUM
Jonathan Richard: Centre de Recherche du CHUM
Bhavna Hora: Duke University Medical Center
Laura Sutherland: Duke University Medical Center
Connie A. Zhao: Dana-Farber Cancer Institute
Brandon P. Conn: Harvard Medical School
Todd Bradley: Duke University Medical Center
M. Anthony Moody: Duke University Medical Center
Bruno Melillo: University of Pennsylvania
Andrés Finzi: Centre de Recherche du CHUM
Barton F. Haynes: Duke University Medical Center
Amos B. Smith: University of Pennsylvania
Sampa Santra: Harvard Medical School
Joseph Sodroski: Dana-Farber Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The “closed,” antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

Date: 2018
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DOI: 10.1038/s41467-018-04758-9

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