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. 2018 Jun 13;23(6):845-854.e6.
doi: 10.1016/j.chom.2018.05.001. Epub 2018 May 31.

Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection

Ian Setliff  1 , Wyatt J McDonnell  2 , Nagarajan Raju  3 , Robin G Bombardi  4 , Amyn A Murji  3 , Cathrine Scheepers  5 , Rutendo Ziki  6 , Charissa Mynhardt  6 , Bryan E Shepherd  7 , Alusha A Mamchak  8 , Nigel Garrett  9 , Salim Abdool Karim  10 , Simon A Mallal  11 , James E Crowe Jr  12 , Lynn Morris  13 , Ivelin S Georgiev  14
Affiliations

Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection

Ian Setliff et al. Cell Host Microbe. .

Abstract

Characterization of single antibody lineages within infected individuals has provided insights into the development of Env-specific antibodies. However, a systems-level understanding of the humoral response against HIV-1 is limited. Here, we interrogated the antibody repertoires of multiple HIV-infected donors from an infection-naive state through acute and chronic infection using next-generation sequencing. This analysis revealed the existence of "public" antibody clonotypes that were shared among multiple HIV-infected individuals. The HIV-1 reactivity for representative antibodies from an identified public clonotype shared by three donors was confirmed. Furthermore, a meta-analysis of publicly available antibody repertoire sequencing datasets revealed antibodies with high sequence identity to known HIV-reactive antibodies, even in repertoires that were reported to be HIV naive. The discovery of public antibody clonotypes in HIV-infected individuals represents an avenue of significant potential for better understanding antibody responses to HIV-1 infection, as well as for clonotype-specific vaccine development.

Keywords: B cells; HIV-1; antibodies; antibody repertoire; computational biology; immunology; next-generation sequencing; public antibodies; systems immunology.

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Figures

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Graphical abstract
Figure 1
Figure 1
Within-Donor Longitudinal Antibody Repertoire Analysis from Pre-infection through Chronic HIV-1 Infection (A) For each donor, the number of clonotypes unique to each time point is shown, as well as the clonotypes shared between two or all three time points. (B) Heatmap of V-gene usage by donor and time point. For each time point of each donor, the number of clonotypes using each VH gene (excluding orphan genes) was summed and the Z score was calculated. Z scores range from −0.81 (light blue) to 4.26 (dark blue). (C) Heatmap of CDRH3 amino acid length by donor and time point. For each time point of each donor, the number of clonotypes of each CDRH3 length was summed and the Z score was calculated. No sequences had a CDRH3 length of 35 in any sample in this study. Z scores range from −0.90 (light green) to 2.54 (dark green).
Figure 2
Figure 2
Identification of Public Antibody Clonotypes after Infection with HIV-1 (A) Clonal overlap between pre-infection (top left), 6 mpi (top right), and 3 ypi (bottom) samples. The width of the curved bands connecting each pair of samples is proportional to the numbers (tick labels) of antibody clonotypes shared by that donor pair at the given time point. (B) For each of the three time points (x axis), the numbers of public antibody clonotypes (y axis) are plotted for each pair (dots) of donors. ∗∗∗p < 0.001. Error bars: mean ± SEM. (C) For all combinations (dots) of two, three, four, and five donors (x axis), the corresponding numbers of public antibody clonotypes (y axis) across all time points are shown. Error bars: mean ± SEM.
Figure 3
Figure 3
Characterization of a Public HIV-Reactive Antibody Clonotype Shared by Three HIV-Infected Donors (A) Multiple sequence alignment of the CDR1-CDR3 regions of the heavy chain sequences from a three-donor public clonotype. Included are antibodies CAP248_#30 and CAP314_#30, as well as representative CAP351 antibodies CAP351_#8051 and CAP351_#20614, along with IGHV1-69∗12, a top germline allele assignment for all antibodies shown. Dots within the V-gene show identity to germline, while letters show mutations from germline. (B) ELISA binding of CAP248_#30 and CAP314_#30 to ConC gp120 at increasing antibody concentrations (x axis), with antibodies VRC01 and PGT128 as positive controls, and PGT151 as a negative control. Error bars: mean ± SD. (C) ELISA binding at a concentration of 1.11 μg/mL of antibodies CAP248_#30 and CAP314_#30 to a wild-type ConC gp120 protein, ConC gp120 with a N332A mutation, and ConC gp120 with a D368R mutation. Control antibodies are VRC01 (D368R sensitive), PGT128 (N332A sensitive), and PGT151 (negative control). Error bars: mean ± SD.
Figure 4
Figure 4
Comparison of Published Antibody Repertoires to Known HIV-Reactive Antibody Sequences (A) Number of donors (size of dots) with antibody heavy chain sequences with identical V-gene assignment, signature sequence features, and CDRH3 identity (y axis) of at least 70% to a set of known HIV-reactive antibodies (x axis). (B) Antibody heavy chain sequences with identical V-gene assignment, signature sequence features, and CDRH3 distance of at most two amino acids. For each pair of known/query antibody sequences, shown are the source dataset, references, V-gene assignment, percentage identity to germline, and CDRH3 length and alignment. V-gene deviation from germline for sequences obtained from the PDB was determined from amino acid sequence using IMGT/DomainGapAlign (Ehrenmann and Lefranc, 2011).
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