Wang H, Chen X, Wang D, Yao C, Wang Q, Xie J, Shi X, Xiang Y, Liu W, Zhang L, (click to view)
The Journal of biological chemistry 2017 11 29() pii 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 remains 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 Env 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.