Development of Antibodies with Broad Neutralization Specificities against HIV-1 after Long Term SHIV Infection in Macaques.

Nan Gao,Feng Gao,Xin Zhang,Lina Meng,Chuan Qin,Wei Wang,Xianghui Yu,Yanxin Gai,Chu Wang

doi:10.3390/v12020163

Abstract

Non-human primates (NHP) are the only animal model suitable to evaluate the protection efficacy of HIV-1 vaccines. It is important to understand how and when neutralizing antibodies (nAbs) with specificities similar to those of human broadly neutralizing antibodies (bnAbs) develop in NHPs. To address these questions, we determined plasma neutralization specificities in two macaques which developed neutralization breadth after long-term simian/human immunodeficiency virus (SHIV) infection and identified neutralization escape mutations by analyzing the env sequences from longitudinal plasma samples. Neutralization activities targeting V2, CD4bs, V3 and gp120-gp41 interface only became detectable in week 350 plasma from macaques G1015R and G1020R using 25710 env mutants. When mapped with CAP45 env mutants, only V2 specificity was detected at week 217 and persisted until week 350 in G1015R. Neutralization escape mutations were found in CD4bs and V2 regions. However, all of them were different from those resistant mutations identified for human bnAbs. These results show that nAbs with specificities similar to human bnAbs are only detectable after long-term SHIV infection and that neutralization escape mutations in macaques are different from those found in HIV-1-infected individuals. These findings can have important implications in the best utilization of the NHP model to evaluate HIV-1 vaccines.

Highlights

Elicitation of broadly neutralizing antibodies against globally diverse HIV-1 strains is likely required for a successful vaccine [1,2,3,4]
A few studies recently showed that potent neutralizing antibodies against autologous viruses with moderate neutralizing breadth could be elicited in different animal models [10,15,16,17,18]
We used a set of eight 25710 env mutants that were known for resistant to neutralization by bnAbs targeting V2 [26,27,32], CD4 binding site (CD4bs) [28,33,34], V3 [35] and gp120-gp41 interface [36,37] to determine when bnAb-like neutralization specificities developed in the plasma of G1015R and G1020R

Summary

Introduction

Elicitation of broadly neutralizing antibodies (bnAbs) against globally diverse HIV-1 strains is likely required for a successful vaccine [1,2,3,4]. Infusion of bnAbs in non-human primates (NHP) and humanized mice prevented acquisition of infection [12,13,14]. Such potent bnAbs have not been successfully elicited in animal models. A few studies recently showed that potent neutralizing antibodies (nAbs) against autologous viruses with moderate neutralizing breadth could be elicited in different animal models [10,15,16,17,18]. Using the epitope focusing approach, a more recent study showed that the FP-coupled carrier protein immunogens could induce cross-reactive

Methods

Results

Conclusion