Analyzing patterns of tyrosine sulfation in naive antibody repertoires

HIV-1 infects a subset of immune cells identified by the receptor CD4 and a coreceptor, CCR5 or CXCR4. Previous studies revealed bnAbs against HIV-1 with antigen-binding sites mimicking binding sites of CCR5. Such antibodies are characterized by post-translationally sulfated tyrosines and anionic motifs in long complementarity determining regions 3 (CDR3s) of the heavy chains. Despite the great therapeutic potential of human antibodies mimicking CCR5, their immunogenetic signatures remain unknown. In this study, we analyzed human naïve heavy chain antibody repertoires and described the most common VDJ recombination scenarios generating CDR3s with sulfated tyrosines and anionic motifs. We showed ~77% of such CDR3s are generated using seven D genes from two families, IGHD3 and IGHD4. We also demonstrated that sulfated tyrosines and anionic motifs are a common feature of mammalian germline D genes.