Induction of Antibodies in Rhesus Macaques That Recognize a Fusion-Intermediate Conformation of HIV-1 gp41

S Moses Dennison,Shi-Mao Xia,Sampa Santra,Peter D Kwong,Laura L Sutherland,Cindy Bowman,Xiaoying Shen,Robert Parks,Richard M Scearce,Gilad Ofek,Bing Chen,Shelley Stewart,Frederick H Jaeger,Barton F Haynes,Yongping Yang,Ruijun Zhang,Norman L Letvin,Georgia D Tomaras ,Shabnam Alam ,Hua‐Xin Liao ,Kara Anasti

doi:10.1371/journal.pone.0027824

Abstract

A component to the problem of inducing broad neutralizing HIV-1 gp41 membrane proximal external region (MPER) antibodies is the need to focus the antibody response to the transiently exposed MPER pre-hairpin intermediate neutralization epitope. Here we describe a HIV-1 envelope (Env) gp140 oligomer prime followed by MPER peptide-liposomes boost strategy for eliciting serum antibody responses in rhesus macaques that bind to a gp41 fusion intermediate protein. This Env-liposome immunization strategy induced antibodies to the 2F5 neutralizing epitope 664DKW residues, and these antibodies preferentially bound to a gp41 fusion intermediate construct as well as to MPER scaffolds stabilized in the 2F5-bound conformation. However, no serum lipid binding activity was observed nor was serum neutralizing activity for HIV-1 pseudoviruses present. Nonetheless, the Env-liposome prime-boost immunization strategy induced antibodies that recognized a gp41 fusion intermediate protein and was successful in focusing the antibody response to the desired epitope.

Highlights

The membrane proximal external region (MPER) of HIV-1 gp41 contains the epitopes of broadly neutralizing antibodies 2F5 and 4E10 [1,2,3,4] that are important targets for HIV-1 vaccine design
MPER-specific broadly neutralizing antibodies are rarely made in HIV-1 infection [8,9] or following HIV-1 envelope protein (Env) vaccination [10,11,12,13]
We have previously reported that MPER epitopes are exposed in JRFL gp140CF Env protein allowing binding of 2F5 and 4E10 mAbs [18]

Summary

Introduction

The membrane proximal external region (MPER) of HIV-1 gp contains the epitopes of broadly neutralizing antibodies 2F5 and 4E10 [1,2,3,4] that are important targets for HIV-1 vaccine design. Structural constraints that include transient exposure of neutralizing epitopes [14,15], as well as immunological tolerance mechanisms [16] are explanations for inability to routinely induce 2F5 or 4E10-like antibody responses. There are two barriers to induction of MPER broad neutralizing antibodies that must be overcome; the transient exposure and poor immunogenicity of subdominant MPER neutralizing epitopes, and tolerance control of the B cells capable of responding to the MPER neutralizing epitopes [16,17]

Methods

Results

Conclusion