A Limited Number of Antibody Specificities Mediate Broad and Potent Serum Neutralization in Selected HIV-1 Infected Individuals

Abstract

A protective vaccine against HIV-1 will likely require the elicitation of a broadly neutralizing antibody (bNAb) response. Although the development of an immunogen that elicits such antibodies remains elusive, a proportion of HIV-1 infected individuals evolve broadly neutralizing serum responses over time, demonstrating that the human immune system can recognize and generate NAbs to conserved epitopes on the virus. Understanding the specificities that mediate broad neutralization will provide insight into which epitopes should be targeted for immunogen design and aid in the isolation of broadly neutralizing monoclonal antibodies from these donors. Here, we have used a number of new and established technologies to map the bNAb specificities in the sera of 19 donors who exhibit among the most potent cross-clade serum neutralizing activities observed to date. The results suggest that broad and potent serum neutralization arises in most donors through a limited number of specificities (1–2 per donor). The major targets recognized are an epitope defined by the bNAbs PG9 and PG16 that is associated with conserved regions of the V1, V2 and V3 loops, an epitope overlapping the CD4 binding site and possibly the coreceptor binding site, an epitope sensitive to a loss of the glycan at N332 and distinct from that recognized by the bNAb 2G12 and an epitope sensitive to an I165A substitution. In approximately half of the donors, key N-linked glycans were critical for expression of the epitopes recognized by the bNAb specificities in the sera.

Identification and specificity of broadly neutralizing antibodies against HIV

“…Indeed, CD4‐binding site bnAb activity emerged in only one subject at 66 months in the protocol C study 7. Of note, other studies have suggested a greater proportion of bnAb serum responses to target the CD4‐binding site 21, 61, 62…”

“…However, simultaneous advances in our ability to discern the specificities that mediate elite neutralization21 advocated for the use of a recombinant Env protein as bait for bnAb B cells. This method was used to identify multiple Ab lineages from six donors but did not identify any with bnAb activity 38.…”

“…High‐throughput neutralization assays were a major factor in changing that situation. The ability to analyze mAb and serum activity against large panels of viruses was demonstrated20 and subsequently used to evaluate large numbers of HIV‐infected donors in the International AIDS Vaccine Initiative (IAVI) Protocol G and C studies to identify those with exceptionally potent and broad sera,8 map the specificities underlying these responses,7, 21 and then isolate bnAbs from these individuals 22, 23, 24, 25, 26, 27, 28. Independently, the standardization of the TZM‐bl neutralization assay and the definition of neutralization sensitivity tiers29, 30, 31 allowed much more rigorous serum analysis.…”

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

“…A number of studies have characterized the antibody specificities mediating plasma neutralization breadth and potency in HIV-1-infected individuals (1,(11)(12)(13). 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).…”

Mouse marginal zone B cells harbor specificities similar to human broadly neutralizing HIV antibodies

“…These broadly neutralizing antibodies are typically highly mutated and often polyreactive (1). Although numerous epitopes on gp120 have been identified as targets of broadly neutralizing antibodies, recent studies of HIVinfected serum demonstrating HIV broadly neutralizing activity have shown that a major neutralizing epitope is directed against the CD4 binding site of gp120 (8)(9)(10). The CD4 binding site is a crucial component of viral attachment and entry into the target cell and is one of the most conserved regions of gp120 (11).…”