New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency

Abstract

The epitopes defined by HIV-1 broadly neutralizing antibodies (bNAbs) are valuable templates for vaccine design, and studies of the immunological development of these antibodies are providing insights for vaccination strategies. In addition, the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of 12 V1V2-directed neutralizing antibodies, CAP256-VRC26, isolated from an HIV-1 clade C-infected donor at years 1, 2, and 4 of infection (N. A. Doria-Rose et al., Nature 509:55-62, 2014, http://dx.doi.org/10.1038/nature13036). Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. Thirteen antibodies were isolated from B cell culture, and eight were isolated using trimeric envelope probes for differential single B cell sorting. One of the new antibodies displayed a 10-fold greater neutralization potency than previously published lineage members. This antibody, CAP256-VRC26.25, neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency. Among the viruses neutralized, the median 50% inhibitory concentration was 0.001 g/ml. All 33 lineage members targeted a quaternary epitope focused on V2. While all known bNAbs targeting the V1V2 region interact with the N160 glycan, the CAP256-VRC26 antibodies showed an inverse correlation of neutralization potency with dependence on this glycan. Overall, our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent. IMPORTANCEStudies of HIV-1 broadly neutralizing antibodies (bNAbs) provide valuable information for vaccine design, and the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of V1V2-directed neutralizing antibodies from an HIV-1 clade C-infected donor. Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. One of the new antibodies, CAP256-VRC26.25, displayed a 10-fold greater neutralization potency than previously described lineage members. It neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency: the median 50% inhibitory concentration was 0.001 g/ml. Our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent.

HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant

“…All infant nAbs had low SHM (2.0–6.6% at the nucleotide level, nt; Figure 7A and Figure S7 ), in contrast to adult bnAbs (3.8–32.6% nt) (Eroshkin et al, 2014; Lefranc et al, 2009) as well as adult nAbs with limited tier 2 neutralizing activity (tier 1 nAbs; 2.4–18.6% nt) (Li et al, 2015). The infant nAbs also had lower SHM than adult nAbs, including those with and without breadth, isolated relatively early pi (1–4 years) from CAP256-VRC26 (4.2–18% nt) (Doria-Rose et al, 2015; Doria-Rose et al, 2014). Overall, infant HIV-specific nAbs are remarkable for the low level of SHM compared to adult nAbs.…”

Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge

“…PGDM1400 and CAP256-VRC26.25 have been shown to neutralize HIV-1 broadly and with high potency (21, 22), but they did not neutralize several commonly used SHIVs (Table 1). We therefore generated a novel challenge stock SHIV-325c by cloning a clade C HIV-1 env sequence from an early HIV-1 infected individual from South Africa (24) into the SHIV KB9-AC backbone.…”

The Neutralizing Antibody Response to the HIV-1 Env Protein

“…Most recently, the design of soluble, recombinant Env trimers and virus-like particles comparable to native Env trimers has provided alternative antigen-specific B cell selection strategies [43–45]. These strategies have enabled the isolation of many dozens of antibodies from elite neutralizers, and some of these have exceptional breadth (approaching 99% of circulating viruses) and potency in the picomolar range [44, 46–48]. As well has providing insights into the host immune response, these remarkable antibodies are now increasingly being tested by passive immunization for either HIV prevention or treatment, with the likelihood of this being successful supported by extensive animal and preclinical human data [38–40, 49–52].…”