Tryptophan 375 stabilizes the outer-domain core of gp120 for HIV vaccine immunogen design

Duoyi Hu,Dane Bowder,Wenzhong Wei,Jesse Thompson,Mark A Wilson,Shi-Hua Xiang

doi:10.1016/j.vaccine.2017.04.054

Abstract

The outer-domain core of gp120 may serve as a better HIV vaccine immunogen than the full-length gp120 because of its greater stability and immunogenicity. In our previous report, we introduced two disulfide bonds to the outer-domain core of gp120 to fix its conformation into a CD4-bound state, which resulted in a significant increase in its immunogenicity when compared to the wild-type outer-domain core. In this report, to further improve the immunogenicity of the outer-domain core based immunogen, we have introduced a Tryptophan residue at gp120 amino acid sequence position 375 (375S/W). Our data from immunized guinea pigs indeed shows a striking increase in the immune response due to this stabilized core outer-domain. Therefore, we conclude that the addition of 375W to the outer-domain core of gp120 further stabilizes the structure of immunogen and increases the immunogenicity.

Highlights

The CD4-binding site (CD4-BS) of gp120 in HIV-1 has been recognized to be the most vulnerable site for antibody targeting and viral neutralization [1,2,3,4,5,6,7,8]
Identification of several potent neutralizing antibodies through the screening of HIV-1 patient sera, such as VRC01 [9] and PGV04 [5], have been known to be elicited by the CD4-BS of gp120. Further analysis of these antibodies has found that the binding sites for some CD4-BS antibodies primarily depend on the outer domain of gp120, which are unlike CD4 binding wherein the binding requires all the three domains: outer domain, inner domain and the bridging sheet [10]
We have further improved the CD4-bound conformation of outer domain mutant 2 (OD2) by adding an additional serine to tryptophan mutation at position 375 (S375W)

Summary

Introduction

The CD4-binding site (CD4-BS) of gp120 in HIV-1 has been recognized to be the most vulnerable site for antibody targeting and viral neutralization [1,2,3,4,5,6,7,8]. Identification of several potent neutralizing antibodies through the screening of HIV-1 patient sera, such as VRC01 [9] and PGV04 [5], have been known to be elicited by the CD4-BS of gp120. Further analysis of these antibodies has found that the binding sites for some CD4-BS antibodies primarily depend on the outer domain of gp120, which are unlike CD4 binding wherein the binding requires all the three domains: outer domain, inner domain and the bridging sheet [10]. The outer domain used as an immunogen has been tested for its immunogenicity previ-

Methods

Results

Conclusion