1. Antibody isotype switching as a mechanism to counter HIV neutralization escape
- Author
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Scheepers, C., Bekker, V., Anthony, C., Richardson, S., Oosthuysen, B., Moyo, T., Kgagudi, P., Kitchin, D., Nonyane, M., Mabvakure, B., Sheng, Z., Lambson, B., Ismail, A., Garrett, N., and Karim, S. Abdool
- Subjects
HIV antibodies -- Genetic aspects ,Antigenic determinants -- Genetic aspects ,Genetic recombination -- Health aspects ,Health - Abstract
Background: Neutralizing antibodies (nAbs) to highly variable vira pathogens show remarkable diversification during infection, resulting in an 'arms race' between virus and host. Somatic hypermutation (SHM) in immunoglobulin variable regions enables maturing antibodies to neutralize emerging viral escape variants. However, antibody diversification also occurs through class-switch recombination (CSR) resulting in intra-lineage isotype variation. The immunoglobulin constant region can influence epitope recognition and viral escape, but whether CSR also contributes to the maturation of natural antibody lineages during the course of HIV infection has not been explored. Methods: Longitudinal deep sequencing of an HIV-directed nAb lineage, CAP88-CH06, identified several co-circulating isotypes (IgG3, IgG1, IgA1, IgG2 and IgA2), some of which shared identical variable regions. CAP88-CH06 lineage members were expressed as multiple naturally occurring isotypes and tested for neutralization and binding against longitudinal single-genome derived autologous envelope clones and epitope mutants. Results: We show that higher levels of SHM were associated with improved neutralization potency against the T/F virus, and an increased ability to neutralize viruses from later time points. However, we also show differences in neutralization and binding of autologous viruses and epitope mutants, based on the isotype of the antibody. In all instances, IgG3 and IgA1 isotypes were better able to neutralize longitudinal autologous viruses and epitope mutants than IgG1 versions of the same antibody, in some cases by >70 fold. We further show that CSR directly impacts nAb lineage maturation, with some switches such as IgG3 to IgG1 resulting in reduced neutralization of circulating viruses, creating 'dead-end' antibody sub-lineages. However, these detrimental switches could be rescued by a further CSR event, from IgG1 to IgA1, which restored neutralization capacity of these antibodies, and enabled further lineage maturation. Conclusions: Our data suggest as with SHM, CSR may have beneficia or deleterious outcomes for antibody maturation. In the CAP88-CH06 lineage, a beneficial CSR event following a detrimental switch, a process we term 'switch redemption', enabled the continued maturation of that sub-lineage. Thus, CSR represents an additional immunological mechanism to counter viral escape from HIV-specific antibody responses. Furthermore, vaccine design strategies aimed at promoting class-switch recombination could enhance antibody responses and vaccine efficacy., OA08.01 C. Scheepers (1); V. Bekker (1); C. Anthony (2); S. Richardson (1); B. Oosthuysen (1); T. Moyo (1); P. Kgagudi (1); D. Kitchin (1); M. Nonyane (1); B. Mabvakure [...]
- Published
- 2021
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