Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens.

Kathryn A Mesa,Bin Yu,Gerardo Perez,Terri Wrin,Faruk Sinangil,Christos J Petropoulos,Sara M O’Rourke,Joseph Robinson,Marcus A Conant,Grant H Pogson,Phillip W Berman,David L Alexander,Heidi E Drummer

doi:10.1371/journal.pone.0213409

Kathryn A Mesa, Bin Yu + Show 11 more

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https://doi.org/10.1371/journal.pone.0213409

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Abstract

A major challenge in HIV vaccine development is the identification of immunogens able to elicit broadly neutralizing antibodies (bNAbs). While remarkable progress has been made in the isolation and characterization of bNAbs, the epitopes they recognize appear to be poorly immunogenic. Thus, none of the candidate vaccines developed to date has induced satisfactory levels of neutralizing antibodies to the HIV envelope protein (Env). One approach to the problem of poor immunogenicity is to build vaccines based on envelope (env) genes retrieved from rare individuals termed elite neutralizers (ENs) who at one time possessed specific sequences that stimulated the formation of bNAbs. Env proteins selected from these individuals could possess uncommon, yet to be defined, structural features that enhance the immunogenicity of epitopes recognized by bNAbs. Here we describe the recovery of envs from an EN that developed unusually broad and potent bNAbs. As longitudinal specimens were not available, we combined plasma and provirus sequences acquired from a single time-point to infer a phylogenetic tree. Combining ancestral reconstruction data with virus neutralization data allowed us to sift through the myriad of virus quasi-species that evolved in this individual to identify envelope sequences from the nodes that appeared to define the transition from neutralization sensitive envs to the neutralization resistant envs that occur in EN plasma. Synthetic genes from these nodes were functional in infectivity assays and sensitive to neutralization by bNAbs, and may provide a novel source of immunogens for HIV vaccine development.

Highlights

A major goal of HIV-1 vaccine research is to develop HIV envelope glycoprotein immunogens that will induce broadly neutralizing antibodies
A major hypothesis put forward to account for the inability of candidate HIV vaccines to elicit bNAbs was that the immunogens lacked the quaternary epitopes present only on the trimeric structures associated with spikes on the virus surface [10, 11]
The experiments described represent the first steps in the development of an improved HIV vaccine based on envs closely resembling those known to have previously elicited unusually broad and potent bNAbs in humans

Summary

Introduction

A major goal of HIV-1 vaccine research is to develop HIV envelope glycoprotein immunogens that will induce broadly neutralizing antibodies (bNAbs). Several groups have developed trimeric forms of the HIV envelope protein that appear to closely resemble the spike proteins [12,13,14,15,16] These proteins possess the epitopes recognized by all of the major classes of bNAbs, and represent a significant advance over the monomeric envelopes tested previously [17, 18]. It is likely that only rare envelope proteins possess the specific biophysical features that define the immunogenic structure required to elicit the formation of bNAbs

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