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

Navid Madani,Barton F Haynes,Todd Bradley,Shilei Ding,Joseph Sodroski,Amy M Princiotto,Jérémie Prevost,Sampa Santra,Jonathan Richard,Bruno Melillo,Laura Sutherland,Linh Mach,Amos B Smith Iii,Brandon P Conn,Connie A Zhao,M Anthony Moody,Andrés Finzi,Bhavna Hora

doi:10.1038/s41467-018-04758-9

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.

Highlights

The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells
Group 1 monkeys were immunized with human serum albumin (HSA) and were challenged with simian-human immunodeficiency virus (SHIV)-C5 mixed with the CD4-mimetic compounds (CD4mc), BNM-III-170
The titers of anti-Env antibodies in the sera of the Group 2 and Group 3 monkeys immunized with HIV-1CH505 gp[120] were comparable (Supplementary Fig. 2). These sera did not efficiently neutralize primary HIV-1 in the absence of the CD4mc, but inhibited the infection of heterologous primary viruses that were sensitized by incubation with sub-neutralizing concentrations of BNM-III-170 (Fig. 2 and Supplementary Table 2)

Summary

Introduction

The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. We test whether vaccination with HIV-1 gp[120] immunogens can confer protection against a stringent challenge with a heterologous simian-human immunodeficiency virus (SHIV-C5)[39] that has been sensitized by a CD4mc, BNM-III-17031 (Fig. 1). Group 1 monkeys were immunized with human serum albumin (HSA) and were challenged with SHIV-C5 mixed with the CD4mc, BNM-III-170.

Results

Conclusion