Ability To Develop Broadly Neutralizing HIV-1 Antibodies Is Not Restricted by the Germline Ig Gene Repertoire

Abstract

The human immunoglobulin repertoire is vast, producing billions of unique antibodies from a limited number of germline immunoglobulin genes. The immunoglobulin heavy chain variable region (IGHV) is central to antigen binding and is comprised of 48 functional genes. Here we analyzed whether HIV-1 infected individuals who develop broadly neutralizing antibodies show a distinctive germline IGHV profile. Using both 454 and Illumina technologies we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Center for the AIDS Programme of Research in South African (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing antibodies. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of monoclonal antibodies isolated from 7 of the CAPRISA women and previously isolated broadly neutralizing antibodies from other donors provided evidence that at least 8 novel or non-IMGT alleles contributed to functional antibodies. Importantly, we found that despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing antibodies, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing antibodies. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive immunoglobulin database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing antibody development in HIV-1 infection, with implications for HIV vaccine design.

Broadly neutralizing human monoclonal JC polyomavirus VP1–specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy

“…We did not find other examples of CNS infections where broadly neutralizing antibodies developed during the course of infection; however, such antibodies arise in HIV-infected individuals independent of their germline repertoire (56) and are characterized by long heavy-chain complementarity-determining region 3 (CDR3), polyreactivity, and high levels of somatic mutations (57), which is also the case for the antibodies described here.…”

Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity

“…The second technique utilized the approach described by previous groups and involved identifying the presence of the same sequence in more than one individual715. Of the 35 sequences that shared identity with germline sequences, 28 were present in at least one of the three additional monkeys analysed (rhesus nos 2514, 2636 and 5200), indicating that this approach could confirm germline alleles.…”

“…Immunological diversity at the level of Ig alleles is now recognized as a factor of some importance12. Studies involving different ethnic groups have revealed novel human VH alleles1518 and comprehensive screening procedures may uncover many additional examples. Additionally, the availability of comprehensive Ig databases for laboratory animals commonly used in immunological research would enable antibody analysis to be extended to these species.…”

Repertoire comparison of the B‐cell receptor‐encoding loci in humans and rhesus macaques by next‐generation sequencing

“…Recent evidence suggests far more geographic IGHV allelic variation than was previously thought. 66 Additionally, the makeup of B-cell repertoires can be influenced by sex and age, and although the animals used in this study were approximately the same age and life stage of the humans, the differences in actual age may confound our analysis. Reporting the repertoires as gene family (as we have done here) likely mitigates these variations, but inclusion of geographically disparate samples and larger age ranges in subsequent studies will be a necessary future step.…”