Somatic hypermutation to counter a globally rare viral immunotype drove off-track antibodies in the CAP256-VRC26 HIV-1 V2-directed bNAb lineage
| Autor: | Kevin Wiehe, Peter D. Kwong, Jason Gorman, Penny L. Moore, Jinal N. Bhiman, David Sacks, Lynn Morris |
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| Rok vydání: | 2019 |
| Předmět: |
Physiology
HIV Infections HIV Antibodies medicine.disease_cause Biochemistry Epitope Database and Informatics Methods Epitopes Immune Physiology HIV Seropositivity Medicine and Health Sciences Chemical Neutralization Biology (General) Genetics 0303 health sciences Mutation Immune System Proteins Crystallography Physics Microbial Mutation 030302 biochemistry & molecular biology Chemical Reactions env Gene Products Human Immunodeficiency Virus Condensed Matter Physics 3. Good health Chemistry Viral evolution Physical Sciences Crystal Structure Female Sequence Analysis Research Article Evolutionary Immunology Lineage (genetic) Bioinformatics QH301-705.5 Immunology Somatic hypermutation Biology Research and Analysis Methods Microbiology Antibodies Viral Evolution Immunophenotyping Affinity maturation 03 medical and health sciences Antigen Neutralization Tests Virology medicine Solid State Physics Humans Amino Acid Sequence Antigens Molecular Biology 030304 developmental biology Evolutionary Biology Biology and Life Sciences Proteins HIV RC581-607 Antibodies Neutralizing Organismal Evolution Epitope mapping Microbial Evolution HIV-1 Parasitology Immunologic diseases. Allergy Sequence Alignment Broadly Neutralizing Antibodies Epitope Mapping |
| Zdroj: | PLoS Pathogens, Vol 15, Iss 9, p e1008005 (2019) PLoS Pathogens |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1008005 |
| Popis: | Previously we have described the V2-directed CAP256-VRC26 lineage that includes broadly neutralizing antibodies (bNAbs) that neutralize globally diverse strains of HIV. We also identified highly mutated “off-track” lineage members that share high sequence identity to broad members but lack breadth. Here, we defined the mutations that limit the breadth of these antibodies and the probability of their emergence. Mutants and chimeras between two pairs of closely related antibodies were generated: CAP256.04 and CAP256.25 (30% and 63% breadth, respectively) and CAP256.20 and CAP256.27 (2% and 59% breadth). Antibodies were tested against 14 heterologous HIV-1 viruses and select mutants to assess breadth and epitope specificity. A single R100rA mutation in the third heavy chain complementarity-determining region (CDRH3) introduced breadth into CAP256.04, but all three CAP256.25 heavy chain CDRs were required for potency. In contrast, in the CAP256.20/27 chimeras, replacing only the CDRH3 of CAP256.20 with that of CAP256.27 completely recapitulated breadth and potency, likely through the introduction of three charge-reducing mutations. In this individual, the mutations that limited the breadth of the off-track antibodies were predicted to occur with a higher probability than those in the naturally paired bNAbs, suggesting a low barrier to the evolution of the off-track phenotype. Mapping studies to determine the viral immunotypes (or epitope variants) that selected off-track antibodies indicated that unlike broader lineage members, CAP256.20 preferentially neutralized viruses containing 169Q. This suggests that this globally rare immunotype, which was common in donor CAP256, drove the off-track phenotype. 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 may facilitate the selection of immunogens that elicit bNAbs and minimize off-track antibodies. Author summary Broadly neutralizing antibodies (bNAbs) develop in some HIV infected individuals, partly due to their complex evolutionary pathways that are characterized by extensive somatic hypermutation (SHM). Furthermore, bNAbs within a lineage may form a minor subset, amidst many strain-specific “siblings”, indicating that minor sequence differences between lineage members can significantly affect neutralization. Here, we define mutations that limit breadth in two “off-track” members of the CAP256-VRC26 bNAb lineage, and show that these occur with relatively high probability. A dominant autologous virus with a globally rare V2 sequence appears to have selected for an off-track antibody, providing a mechanism for the development of this antibody during infection. These data highlight the complex interdependencies between high levels of SHM and breadth, as mutations that neutralize autologous viruses may limit heterologous breadth. Consequently, strategies to increase SHM by repeated vaccinations will require careful antigen selection to focus the humoral response to globally common epitopes, limiting off-track responses. |
| Databáze: | OpenAIRE |
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