Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection

Abstract

Objective: Studies of neutralizing antibodies in HIV-1 infected individuals provide insights into the quality of the response that should be possible to elicit with vaccines and ways to design effective immunogens. Some individuals make high titres of exceptional broadly reactive neutralizing antibodies that are of particular interest; however, more modest responses may be a reasonable goal for vaccines. We performed a large cross-sectional study to determine the spectrum of neutralization potency and breadth that is seen during chronic HIV-1 infection.

Design: Neutralization potency and breadth were assessed with genetically and geographically diverse panels of 205 chronic HIV-1 sera and 219 Env-pseudotyped viruses representing all major genetic subtypes of HIV-1.

Methods: Neutralization was measured by using Tat-regulated luciferase reporter gene expression in TZM-bl cells. Serum-neutralizing activity was compared with a diverse set of human mAbs that are widely considered to be broadly neutralizing.

Results: We observed a uniform continuum of responses, with most sera displaying some level of cross-neutralization, and approximately 50% of sera neutralizing more than 50% of viruses. Titres of neutralization (potency) were highly correlated with breadth. Many sera had breadth comparable to several of the less potent broadly neutralizing human mAbs.

Conclusion: These results help clarify the spectrum of serum-neutralizing activity induced by HIV-1 infection and that should be possible to elicit with vaccines. Importantly, most people appear capable of making low to moderate titres of broadly neutralizing antibodies. Additional studies of these relatively common responses might provide insights for practical and feasible vaccine designs.

Fig. 1. Variation in serum neutralization potency and virus susceptibility

(a) Heatmap displaying ID50 titres from 205 chronic donor sera (columns) tested against 229 phylogenetically diverse Env-pseudotyped viruses (rows). (b) Heatmaps comparing 10 bnAbs tested against 103 diverse viruses, and the 205 chronic donor sera assayed with the same set of 103 viruses. Columns in both heatmaps are ordered with greatest potencies to the left. Rows are ordered with greatest virus susceptibilities at the top. Neutralization titres of bnAbs and sera are presented separately because their different units are not directly comparable (i.e. concentration for bnAbs, dilution for sera). For bnAbs, lower values represent more potent neutralization, whereas for serum samples, higher values represent more potent neutralization. The column order of bnAbs follows that of columns in Table 1 (10E8 to 2G12 from left to right). Colour-key histograms (left and right histograms are for serum samples, middle histogram is for bnAbs) summarize the percentage of the total number of reactions that fell within a given range of neutralization titres. Annotation bands indicate virus clades (left column), serum clades (coloured bars, immediately above heatmaps for all 205 samples) and the 88 prescreened sera (grey bars above the colored bars). An ‘x’ indicates missing data.

Fig. 2. Serum neutralization breadth and potency continuum

(a) Breadth and potency of neutralization were highly correlated among the 117 nonprescreened sera (Spearman rank correlation, P = 2.8 × 10⁻³⁴, ρ = 0.85), though a few sera had exceptionally high potency. Circles indicate sera profiled in (e), selected for having breadths that match representative human bnAbs. (b) Breadth and potency were highly correlated among 88 sera selected by prescreening (Spearman rank correlation, P = 4.1× 10⁻²¹, ρ = 0.80); a few sera again had exceptionally high potency. (c) Serum percentiles on the y-axis showing the proportion of 117 nonprescreened sera with equal or greater breadth than the breadth shown along the x-axis. Breadths of four representative bnAbs are superimposed for comparison (b12, 2F5, PGT128, 4E10). Serum breadths were consistent with a uniform distribution (Kolmogorov test, P = 0.31, approximated due to 27 ties). (d) Breadth and potency of 10 bnAbs. (e) Magnitude-breadth functions showing proportion of viruses neutralized versus ID50 titre for 10 sera having breadths that match representative bnAbs. (f) Magnitude-breadth functions of 10 representative bnAbs.