Structural and genetic convergence of HIV-1 neutralizing antibodies in vaccinated non-human primates.

Fangping Cai,Amanda Eaton,Weimin Wu,Barton F Haynes,Xiaoying Shen,Neelakshi Gohain,Michael S Seaman,Kshitij Wagh,Natalia De Val,Misook Choe,Sampa Santra,David C Montefiori,Kevin Wiehe,Julia A Jones,Bette Korber,Kevin O Saunders,Mattia Bonsignori,Esther M Lee,Georgia D Tomaras,M Anthony Moody,Nelson R Wu,Richard M Scearce ,Laura L Sutherland ,Wei‐Hung Chen ,Michael Joyce ,Giovanna Hernandéz ,Celia C Labranche

doi:10.1371/journal.ppat.1009624

Abstract

A primary goal of HIV-1 vaccine development is the consistent elicitation of protective, neutralizing antibodies. While highly similar neutralizing antibodies (nAbs) have been isolated from multiple HIV-infected individuals, it is unclear whether vaccination can consistently elicit highly similar nAbs in genetically diverse primates. Here, we show in three outbred rhesus macaques that immunization with Env elicits a genotypically and phenotypically conserved nAb response. From these vaccinated macaques, we isolated four antibody lineages that had commonalities in immunoglobulin variable, diversity, and joining gene segment usage. Atomic-level structures of the antigen binding fragments of the two most similar antibodies showed nearly identical paratopes. The Env binding modes of each of the four vaccine-induced nAbs were distinct from previously known monoclonal HIV-1 neutralizing antibodies, but were nearly identical to each other. The similarities of these antibodies show that the immune system in outbred primates can respond to HIV-1 Env vaccination with a similar structural and genotypic solution for recognizing a particular neutralizing epitope. These results support rational vaccine design for HIV-1 that aims to reproducibly elicit, in genetically diverse primates, nAbs with specific paratope structures capable of binding conserved epitopes.

Highlights

In a recent nonhuman primate vaccine study, vaccine-elicited HIV-1 neutralizing antibodies (nAbs) titers were shown to correlate with protection from the vaccine-matched challenge virus [1]
We characterized the structure and genetic features of HIV-1 inhibitory antibodies from vaccinated monkeys as a model for human vaccination
We found that individual monkeys responded to HIV vaccination by generating highly similar HIV-1 neutralizing antibodies

Summary

Introduction

In a recent nonhuman primate vaccine study, vaccine-elicited HIV-1 nAb titers were shown to correlate with protection from the vaccine-matched challenge virus [1]. Antibodies that target highly conserved epitopes on HIV-1 envelope glycoprotein are capable of neutralizing diverse HIV-1 isolates and are designated as broadly neutralizing antibodies (bnAbs) [7,8,9] These bnAbs are rarely elicited by vaccination in primates [10,11], and in the select cases where they have been induced, they appear at low titers [12,13]. Another category of nAbs are antibodies capable of neutralizing only the HIV-1 strain used for vaccination or infection— referred to as the autologous virus [1,14,15,16]. These autologous neutralizing antibodies have been more readily elicited with vaccination than bnAbs

Methods

Results

Discussion

Conclusion