The Neutralization Breadth of HIV-1 Develops Incrementally over Four Years and Is Associated with CD4 ⁺ T Cell Decline and High Viral Load during Acute Infection

Abstract

؉ T cell decline, viral load, and CD4 ؉ T cell count at 6 months postinfection but not at later time points, suggesting that early events set the stage for the development of breadth. However, in a multivariate analysis, CD4 decline was the major driver of this association, as viral load was not an independent predictor of breadth. Mapping of the epitopes targeted by cross-neutralizing antibodies revealed that in one individual these antibodies recognized the membrane-proximal external region (MPER), while in two other individuals, cross-neutralizing activity was adsorbed by monomeric gp120 and targeted epitopes that involved the N-linked glycan at position 332 in the C3 region. Serum antibodies from the other four participants targeted quaternary epitopes, at least 2 of which were PG9/16-like and depended on the N160 and/or L165 residue in the V2 region. These data indicate that fewer than 20% of HIV-1 subtype C-infected individuals develop antibodies with cross-neutralizing activity after 3 years of infection and that these antibodies target different regions of the HIV-1 envelope, including as yet uncharacterized epitopes.

Rapid development of glycan-specific, broad, and potent anti–HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque

“…Our epitope-mapping studies indicate that the plasma bNAbs bind to an epitope critically dependent on the gp120 N332 glycan, perhaps overlapping that of 2G12 and/or the recently described PGT antibodies. Importantly, broad and potent serum-neutralizing activity in a significant proportion of HIV-1-infected donors has been mapped to N332A-sensitive epitopes (13,14), and broad and highly potent monoclonal antibodies have recently been isolated from such donors (19). Given the rapid generation of bNAbs in this macaque, and the prevalence of bNAbs against N332A-sensitive epitopes in humans, it will be of interest to determine whether bNAbs against glycan epitopes are more rapidly elicited during natural infection and whether they can be more easily induced by vaccination.…”

“…Notably, the N332 glycan is important for formation of the epitopes recognized by the glycan-specific bNAb 2G12 and the recently described PGT bNAbs (18,19). Furthermore, serum-mapping studies have demonstrated that this glycan is critical for broad and potent serumneutralizing activity in a significant proportion of HIV-1-infected humans (13,14 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 <100 >2700 400 >2700 1800 >2700 <100 >2700 <100…”

“…Furthermore, a few longitudinal studies have examined the factors associated with the development of breadth, and although there are some inconsistencies, it has been suggested that broad neutralization correlates with time postinfection, plasma viremia levels, CD4 + T-cell counts at set-point, and binding avidity to the envelope protein (1,14,15). Though these studies have provided some insight into the factors associated with the development of bNAbs, detailed longitudinal studies involving bNAbs of different specificities would greatly improve our understanding of the evolution and maturation of broad responses.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Breadth of plasma neutralizing activity develops incrementally,48 and evidence suggests that protracted exposure to HIV‐1 Env is required 22, 23, 24, 47, 48, 49, 50. Neutralization breadth is not an all‐or‐nothing phenomenon—in one study, about half of a cohort of 205 chronically infected persons were capable of neutralizing about half of a panel of 219 hard‐to‐neutralize (tier 2) HIV‐1 isolates 45.…”

On the benefits of sin

“…36,37 response during HIV infection. One of the most basic examples that anti-HIV humoral immune responses are susceptible to original antigenic sin was observed following vaccination with HIV-1 SF2 gp120.…”