The breadth of HIV-1 neutralizing antibodies depends on the conservation of key sites in their epitopes.

Hongjun Bai,Morgane Rolland,Merlin L Robb,Nelson L Michael,Yifan Li,Roland R Regoes

doi:10.1371/journal.pcbi.1007056

Hongjun Bai, Morgane Rolland + Show 4 more

Open Access

https://doi.org/10.1371/journal.pcbi.1007056

Copy DOI

Abstract

Developing HIV-1 vaccines that trigger broadly neutralizing antibodies (bnAbs) is a priority as bnAbs are considered key to elicitation of a protective immune response. To investigate whether the breadth of a neutralizing antibody (nAb) depended on the conservation of its epitope among circulating viruses, we examined Antibody:Envelope (Ab:Env) interactions and worldwide Env diversity. We found that sites corresponding to bnAb epitopes were as variable as other accessible, non-hypervariable Env sites (p = 0.50, Mann-Whitney U-test) with no significant relationship between epitope conservation and neutralization breadth (Spearman’s ρ = -0.44, adjusted p = 0.079). However, when accounting for key sites in the Ab:Env interaction, we showed that the broadest bnAbs targeted more conserved epitopes (Spearman’s ρ = -0.70, adjusted p = 5.0e-5). Neutralization breadth did not stem from the overall conservation of Ab epitopes but depended instead on the conservation of key sites of the Ab:Env interaction, revealing a mechanistic basis for neutralization breadth that could be exploited for vaccine design.

Highlights

There is an urgent need for a vaccine against HIV-1
We tested the relationship between HIV1 diversity and neutralization breadth
While bnAbs did not target more conserved regions of HIV-1 Env, we found that the broadest bnAbs relied forcibly more on structural interactions at key sites of the Ab:Env interaction than other Abs

Summary

Introduction

There is an urgent need for a vaccine against HIV-1. Since HIV-1 shows remarkable diversity, it is assumed that a vaccine should elicit bnAbs to block the most extensive array of HIV-1 strains[1,2,3,4]. A number of studies have focused on the fraction of individuals who can develop bnAbs that can neutralize a majority of the viruses in a panel[6,7,8,9]. These bnAbs arise after Ab lineages have matured typically over multiple years[5, 10,11,12,13]. VRC01 was isolated from patient 45, an African-American male who had been infected with HIV-1 subtype B for 11 years at the time of Ab isolation; he was considered a long term non-progressor as his viremia was maintained around 10,000 copies/ml [14]. BnAbs recognize exposed regions of the Env trimer and tend to target five sites: the V1V2-glycan site (e.g. PG9), the V3-glycan site (e.g. PGT128), the CD4 binding site (e.g. VRC01), the gp120-gp interface (e.g. 8ANC195, 35O22) and the membrane proximal region of Env-gp (e.g. 10E8) [16]

Methods

Results

Discussion

Conclusion