Epitope-focused immunogens against the CD4-binding site of HIV-1 envelope protein induce neutralizing antibodies against auto- and heterologous viruses

Hua Wang,Xiangjun Chen,Dianhong Wang,Chen Yao,Qian Wang,Jiayu Xie,Xuanling Shi,Ye Xiang,Wanli Liu,Linqi Zhang

doi:10.1074/jbc.m117.816447

Abstract

Recent discoveries of broadly neutralizing antibodies (bnAbs) in HIV-1-infected individuals have led to the identification of several major "vulnerable sites" on the HIV-1 envelope (Env) glycoprotein. These sites have provided precise targets for HIV-1 vaccine development, but identifying and utilizing many of these targets remain technically challenging. Using a yeast surface display-based approach, we sought to identify epitope-focused antigenic domains (EADs) containing one of the "vulnerable sites," the CD4-binding site (CD4bs), through screening and selection of a combinatorial antigen library of the HIV-1 envelope glycoprotein with the CD4bs bnAb VRC01. We isolated multiple EADs and found that their trimeric forms have biochemical and structural features that preferentially bind and activate B cells that express VRC01 in vitro More importantly, these EADs could induce detectable levels of neutralizing antibodies against genetically related autologous and heterologous subtype B viruses in guinea pigs. Our results demonstrate that an epitope-focused approach involving a screen of a combinatorial antigen library is feasible. The EADs identified here represent a promising collection of possible targets in the rational design of HIV-1 vaccines and lay the foundation for harnessing the specific antigenicity of CD4bs for protective immunogenicity in vivo.

Highlights

Recent discoveries of broadly neutralizing antibodies in HIV-1–infected individuals have led to the identification of several major “vulnerable sites” on the HIV-1 envelope (Env) glycoprotein
The epitopefocused antigenic domains (EADs) identified here represent a promising collection of possible targets in the rational design of HIV-1 vaccines and lay the foundation for harnessing the specific antigenicity of CD4-binding site (CD4bs) for protective immunogenicity in vivo
As many of the epitopes are conformational in nature, carving them out from the entire envelope glycoprotein while maintaining and stabilizing their native structures remains a technical challenge

Summary

To whom correspondence should be addressed

Immune responses are believed to play critical roles in combating infection, it has been widely theorized that a successful vaccine should elicit a potent, sustainable neutralizing antibody response against a broad range of circulating HIV-1 strains [1, 2]. Recent scientific advances have led to the identification of a growing number of broadly neutralizing antibodies (bnAbs) against HIV-1, which in turn have provided critical insights into the protective mechanisms of the human immune system and precise targets for immunogen design [3, 4] Speaking, these bnAbs recognized five major “vulnerable sites” on the HIV-1 envelope glycoprotein gp160 as follows: 1) the CD4binding site (CD4bs); 2) the glycan-associated V1V2; 3) V3 subdomains of gp120; 4) the membrane proximal external region (MPER) of gp; and 5) the interface between gp120 and gp41 [5,6,7]. The EAD-VRC01 identified here could serve as a promising prototype for the future HIV-1 vaccines aiming to translate the specific antigenicity of CD4bs into the protective immunogenicity in vivo

Results

Discussion

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