Probabilities of HIV-1 bNAb development in healthy and chronically infected individuals

Abstract

HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we performed unbiased sequence analyses of B cell receptor repertoires from 57 healthy and 46 chronically HIV-1- or HCV-infected individuals and learned probabilistic models to predict the likelihood of bNAb development. We show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking of bNAbs by their probabilities allowed to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we found equal bNAb probabilities across infected and healthy donors. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in healthy individuals.

Dissecting the impact of somatic hypermutation on SARS-CoV-2 neutralization and viral escape

“…Immunoglobulin heavy, kappa, and lambda chain variable (IGHV, IGKV, and IGLV) gene segments usages reflected the SARS-CoV-2characteristic overrepresentation of distinct V genes (e.g., IGHV3-53, IGHV3-66, IGKV3-20, and IGLV6-57) with a kappa to lambda ratio of approximately 2:1 (Supplementary Figure 1). CDR3 length distributions were comparable to reference memory B cell IgG repertoire data 68 (Supplementary Figure 1). We recombinantly expressed all 92 original wild-type (WT) antibodies as well as the 88 possible VH/VL region germline-reverted (GL) versions (four antibodies with no mutations were used as internal controls) and compared their binding and neutralization activity by Wu01 S-Protein ELISA and pseudo-typed lentivirus neutralization tests.…”

“…To evaluate the impact of somatic hypermutation on the functionality of SARS-CoV-2 antibodies, we selected 92 monoclonal antibodies from the CoV-AbDab, 67 which were isolated from at least 33 individuals in 16 distinct studies between 2020 and 2021 and comprise 62 unique VH/VL pairings as well as 86 unique heavy chain complementarity determining region (CDR) 3 sequences (Figure 1A, Supplementary Table 1). The selected antibodies mainly targeted the receptorbinding domain (RBD, 90/92; Figure 1B, Supplementary Table 1) and overall carried less mutations than the average memory B cell IgG repertoire 68 6 [IQR: 3 -8] amino acid substitutions in heavy, kappa, and lambda chains, respectively; Figure 1C). Immunoglobulin heavy, kappa, and lambda chain variable (IGHV, IGKV, and IGLV) gene segments usages reflected the SARS-CoV-2characteristic overrepresentation of distinct V genes (e.g., IGHV3-53, IGHV3-66, IGKV3-20, and IGLV6-57) with a kappa to lambda ratio of approximately 2:1 (Supplementary Figure 1).…”

Inspecting the interaction between human immunodeficiency virus and the immune system through genetic turnover

“…For example, previous work has studied the dynamics of HIV variants escaping the immune system [20][21][22], or diversity patterns and linkage equilibrium properties of the virus [23]. On the immune system side, a large body of work has been dedicated to studying the immune response to HIV and the emergence of bNAbs [24][25][26], as well as to characterize lineage evolution during the affinity maturation process, using high-throughput sequencing of B-cell repertoire [27,28]. Much less work focuses on the coupled evolutionary dynamics of the two populations.…”

Inspecting the interaction between HIV and the immune system through genetic turnover

“…For example, previous work has studied the dynamics of HIV variants escaping the immune system [20–22], or diversity patterns and linkage equilibrium properties of the virus [23]. On the immune system side, a large body of work has been dedicated to studying the immune response to HIV and the emergence of broadly neutralizing antibodies [24–26], as well as to characterize lineage evolution during the affinity maturation process, using high-throughput sequencing of B-cell repertoire [27, 28]. Much less work focuses on the coupled evolutionary dynamics of the two populations.…”