Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains

作者：Zhu Jiang; Ofek Gilad; Yang Yongping; Zhang Baoshan; Louder Mark K; Lu Gabriel; McKee Krisha; Pancera Marie; Skinner Jeff; Zhang Zhenhai; Parks Robert; Eudailey Joshua; Lloyd Krissey E; Blinn Julie; Alam S Munir; Haynes Barton F; Simek Melissa; Burton Dennis R; Koff Wayne C; Mullikin James C; Mascola John R; Shapiro Lawrence^*; Kwong Peter D

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(16): 6470-6475.

DOI：10.1073/pnas.1219320110

• antibody-affinity maturation
• antibodyomics
• B-cell ontogeny
• DNA sequencing
• immunological tolerance

Next-generation sequencing of antibody transcripts from HIV-1-infected individuals with broadly neutralizing antibodies could provide an efficient means for identifying somatic variants and characterizing their lineages. Here, we used 454 pyrosequencing and identity/divergence grid sampling to analyze heavy- and light-chain sequences from donor N152, the source of the broadly neutralizing antibody 10E8. We identified variants with up to 28% difference in amino acid sequence. Heavy- and light-chain phylogenetic trees of identified 10E8 variants displayed similar architectures, and 10E8 variants reconstituted from matched and unmatched phylogenetic branches displayed significantly lower autoreactivity when matched. To test the generality of phylogenetic pairing, we analyzed donor International AIDS Vaccine Initiative 84, the source of antibodies PGT141-145. Heavy- and light-chain phylogenetic trees of PGT141-145 somatic variants also displayed remarkably similar architectures; in this case, branch pairings could be anchored by known PGT141-145 antibodies. Altogether, our findings suggest that phylogenetic matching of heavy and light chains can provide a means to approximate natural pairings.

• 出版日期2013-4-16
• 单位MIT; NIH