Diverted Antibody Evolution – implications for bnAbs
A recent study, published in PLoS Pathogens by NICD PhD student David Sacks, shows how somatic hypermutation to counter a globally rare viral sequence drove off-track antibodies in the CAP256-VRC26 bnAb lineage. bnAbs develop in only a few HIV infected individuals. Their development is complicated by complex evolutionary pathways that are characterized by extensive somatic hypermutation of antibodies.
Previous work by Jinal Bhiman showed that CAP256-VRC26 lineage includes both bnAbs and highly mutated “off-track” lineage members that share high sequence identity to broad members but lack breadth.
In this study, Sacks defined the specific mutations that limit breadth in two “off-track” members of the CAP256-VRC26 bNAb lineage, and showed that these occur with a relatively high probability. He also showed how a dominant virus within the CAP256 donor, that had a globally rare V2 sequence, selected for an off-track antibody, providing a mechanism for the development of this antibody during infection.
These data show that affinity maturation to counter globally rare viral immunotypes can drive antibodies within a broad lineage along multiple pathways towards strain-specificity. Defining developmental pathways towards and away from breadth will facilitate the selection of immunogens that elicit bnAbs and minimize off-track antibodies.
For further reading: Sacks D, et al. Somatic hypermutation to counter a globally rare viral immunotype drove off-track antibodies in the CAP256-VRC26 HIV-1 V2-directed bNAb lineage. PLoS Pathogens. 2019;15(9):e1008005. doi: 10.1371/journal.ppat.1008005. https://www.ncbi.nlm.nih.gov/pubmed/31479499