Two distinct broadly neutralizing antibody specificities of different clonal lineages in a single HIV-1-infected donor: implications for vaccine design

Abstract

Plasma from a small subset of subjects chronically infected with HIV-1 shows remarkable magnitude and breadth of neutralizing activity. From one of these individuals (CH0219), we isolated two broadly neutralizing antibodies (bnAbs), CH01 and VRC-CH31, from two clonal lineages of memory B cells with distinct specificities (variable loop 1 and 2 [V1V2] conformational specificity and CD4-binding site specificity, respectively) that recapitulate 95% of CH0219 serum neutralization breadth. These data provide proof of concept for an HIV-1 vaccine that aims to elicit bnAbs of multiple specificities.

Fig 1

Phylogenetic tree of the VRC-CH30 to VRC-CH34 monoclonal antibodies. The tree shows the evolutionary distances of the V(D)J nucleotide sequences of the VRC-CH30 to VRC-CH34 monoclonal antibodies and is rooted on the nucleotide sequence of the unmutated common ancestor (UCA) sequence. It is important to note the great distance of each of the mature antibodies from the common UCA sequence, as we previously observed for the CH01 through CH04 MAbs (2).

Fig 2

Comparison of the neutralization profiles of the serum of donor CH0219 and MAbs CH01 and VRC-CH31 either alone or in combination. Neutralizing activity was tested on a panel of 97 Env-pseudotyped lentiviruses, which comprised tier 1 and tier 2 isolates as well as transmitted founder viruses from multiple clades. CH01 and VRC-CH31 MAbs were tested both alone and in combination at a 1:1 ratio. Monoclonal antibody activity is shown as IC₅₀ (μg/ml) and color coded based on the following IC₅₀ ranges: <0.1 (red), 0.1 to 1 (orange), 1.1 to 10 (bright yellow), 11 to 50 (straw yellow), and >50 (white). Serum activity is shown as ID₅₀ titer (1/dilution). Serum neutralization resistance was defined as an ID₅₀ titer less than 20. Concordance of neutralization between the serum and the combination of the CH01 and the VRC-CH31 MAbs is noted as follows: ✓, sensitivity to both serum and the MAb combination; ×, sensitivity to serum only; Δ, sensitivity to the MAb combination only; =, neutralization resistance to both serum and MAb combination. Part of the data for CH01 MAb alone has been previously published (2).

Fig 3

Correlation analysis of neutralization breadths and titers of donor CH0219 serum and the combination of CH01 and VRC-CH31 MAbs. (A) Contingency table showing the numbers of isolates neutralized by serum of donor CH0219 and/or the combination of CH01 and VRC-CH31 MAbs. (B) Linear regression analysis comparing IC₅₀s of the CH01 and VRC-CH31 combination (y axis) and serum ID₅₀ values (x axis).