Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

Abstract

The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers.

Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors

“…In particular, the conformation dependence of the DARPin-target interaction may prove advantageous for selecting potent entry inhibitors with novel specificities, including alternatives to quaternary antibodies (73,74), i.e., targeting epitopes only present on the fully assembled native envelope spike. Once identified, HIV-specific DARPin binders with inhibitory activity open multiple avenues for improving their potency.…”

Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals

“…Furthermore, the observation that MAbs PG9 and PG16 largely recapitulate the neutralizing activity of the donor plasma provides evidence that broad neutralization can occur in some cases via a single specificity or multiple overlapping specificities (111). An overarching question from these studies concerns the number of nAb specificities that typically mediate broad plasma neutralization (72,90,95,112). Here, to gain more insights into the frequency and titer of existing bnAb specificities and possibly to identify new bnAb targets, we analyzed the specificities of plasma samples from 9 HIV-1-infected subjects who exhibited high-titer bnAbs.…”

“…Longitudinal studies have revealed that the virus and the host nAb response continually evolve (11,73,83,86,113). After several years of infection, an estimated 10 to 30% of individuals develop bnAb responses (4,7,28,52,57,66,72,88,89). Although these extraordinary responses have little impact in the setting of established infection, they could have a major impact on transmission if they could be induced by vaccines prior to virus exposure.…”

The Thai Phase III HIV Type 1 Vaccine Trial (RV144) Regimen Induces Antibodies That Target Conserved Regions Within the V2 Loop of gp120

“…39 Broadly neutralizing antibodies that interact with quaternary neutralizing epitopes (QNE) of trimeric native Env spikes have been shown to interact with conserved aa embedded within the variable (V) loops of gp120 including the V2 loop. [40][41][42][43][44][45][46][47] Furthermore, antibodies found in individuals that exhibit potent cross-clade neutralizing activity have been shown to target conserved regions of the V1, V2, and V3 loops, providing evidence that V2 contributes to the formation of QNE that can induce potent cross-clade neutralizing antibodies. 25,43 The structure of scaffolded V1/V2 complexed with the broadly neutralizing monoclonal antibody PG9 has been resolved.…”