Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection
- Fred Hutchinson Cancer Research Center, United States
- University of Washington, United States
- Coast Provincial General Hospital, Kenya
Abstract
Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.
Data availability
* Sequencing data have been deposited at BioProject SRA, accession PRJNA674442.* The EM map and atomic coordinates for QA013.2 complexed to BG505.SOSIP.664 are deposited under accession codes EMD-24195 and PDB 7N65.* Source data have been provided for Figures 2-8.
-
Subject QA013 antibody sequencingBioProject, PRJNA674442.
Article and author information
Author details
Mackenzie M Shipley
Funding
National Institutes of Health (R01 AI140891)
- Jesse D Bloom
National Institutes of Health (R01 AI146028)
- Frederick Matsen IV
National Institutes of Health (U19 AI117891)
- Frederick Matsen IV
National Institutes of Health (U19 AI128914)
- Frederick Matsen IV
National Institutes of Health (R01 AI140868)
- Kelly K Lee
National Institutes of Health (R01 AI138709)
- Julie M Overbaugh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This study (Clinical Trial Management System Number RG1000880) was approved by members of the ethical review committees (file number 7776) at the University of Nairobi, the Fred Hutchinson Cancer Research Center, and the University of Washington. Study participants provided written informed consent prior to enrollment.
Copyright
© 2021, Shipley et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,144
- views
-
- 148
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection
eLife 10:e68110.
https://doi.org/10.7554/eLife.68110
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf.
-
- Microbiology and Infectious Disease
The type VI secretion system (T6SS) is a sophisticated, contact-dependent nanomachine involved in interbacterial competition. To function effectively, the T6SS must penetrate the membranes of both attacker and target bacteria. Structures associated with the cell envelope, like polysaccharides chains, can therefore introduce spatial separation and steric hindrance, potentially affecting the efficacy of the T6SS. In this study, we examined how the capsular polysaccharide (CPS) of Acinetobacter baumannii affects T6SS’s antibacterial function. Our findings show that the CPS confers resistance against T6SS-mediated assaults from rival bacteria. Notably, under typical growth conditions, the presence of the surface-bound capsule also reduces the efficacy of the bacterium’s own T6SS. This T6SS impairment is further enhanced when CPS is overproduced due to genetic modifications or antibiotic treatment. Furthermore, we demonstrate that the bacterium adjusts the level of the T6SS inner tube protein Hcp according to its secretion capacity, by initiating a degradation process involving the ClpXP protease. Collectively, our findings contribute to a better understanding of the dynamic relationship between T6SS and CPS and how they respond swiftly to environmental challenges.
