Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope

Abstract

V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage.IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage.

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

“…Within the CAP256-VRC26 lineage, constrained virus escape was associated with reduced infectivity and altered entry kinetics [111]. This observation is consistent with the likelihood that bNAb epitopes are conserved for functional reasons, with escape likely requiring compensatory mutations [97, 110], and suggests that slower viral escape supports the development of bNAbs through prolonged exposure to antigen [96, 97, 110, 111]. This hypothesis is further supported by the demonstration in vaccine studies that extended antigen availability enhances germinal center activity and resulting neutralizing Ab responses [112, 113].…”

Selective transmission of some HIV-1 subtype C variants might depend on Envelope stimulating dendritic cells to secrete IL-10

“…An important approach of this study was to compare TF from single variant transmission cases to matched CI clones as we hypothesized that transmission of multiple variants were less likely to have undergone selection. Therefore, when CAP177 was shown to be infected by two distinct variants [35], the participant was included in the study to determine whether C3 and C4 also differed in their ability to stimulate IL-10 release. IL-10 secretion varied 32-fold between clones (range = 21 to 680 pg ml -1 ) and 340-fold between donors (range = 2 pg ml -1 to 724 pg ml -1 ).…”

The Neutralizing Antibody Response to the HIV-1 Env Protein

“…Unfortunately, the development of bNAbs confers no clinical benefit to those people in whom they develop, a consequence of the ability of the viruses to escape even these antibodies that must target more conserved epitopes [26]. Escape from bNAbs has been documented in many studies of infected donors who develop breadth [33–37], and also in HIV-1 infected donors passively infused with broadly neutralizing monoclonal antibodies [38–41], though few studies have assessed the fitness costs, if any, of these viral mutations.…”

“…Indeed, in a recent clinical trial of the V3-glycan bNAb 10–1074, over 90% of viruses had escaped within four weeks of infusion [40]. Thus, the intrinsic “escapability” from bNAbs targetting conserved epitopes may also be impacted by a more dynamic interplay of viral fitness and escape in the context of polyclonal plasma [71, 97]. …”