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Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

Journal Article · · Science Translational Medicine
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  1. Duke Univ. School of Medicine, Durham, NC (United States); Duke Human Vaccine Inst., Durham, NC (United States)
  2. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
  3. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  4. Memorial Sloan Kettering Cancer Center, New York, NY (United States)
  5. Duke Human Vaccine Inst., Durham, NC (United States)
  6. Duke Human Vaccine Inst., Durham, NC (United States); Duke Univ. Schoole of Medicine, Durham, NC (United States)
  7. National Inst. of Health (NIH), Bethesda, MD (United States)
  8. National Inst. of Communicable Diseases, Johannesburg (South Africa)
  9. Univ. of Alabama, Burmingham, AL (United States)
  10. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  11. Kamuzu Central Hospital, Lilongwe (Malawi). Univ. of North Carolina Project
  12. Univ. of North Carolina, Chapel Hill, NC (United States)
  13. Boston Univ., MA (United States)
+ Show Author Affiliations
A preventive HIV-1 vaccine should induce HIV-1–specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3- glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3- glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.
Research Organization:
Los Alamos National Laboratory (LANL)
Sponsoring Organization:
National Institutes of Health; USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1406204
Alternate ID(s):
OSTI ID: 1430303
Report Number(s):
LA-UR-16-25421
Journal Information:
Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 381 Vol. 9; ISSN 1946-6234
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (33)

Superinfection Drives HIV Neutralizing Antibody Responses from Several B Cell Lineages that Contribute to a Polyclonal Repertoire journal April 2018
HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage journal November 2017
Multivalent Antigen Presentation Enhances the Immunogenicity of a Synthetic Three-Component HIV-1 V3 Glycopeptide Vaccine journal May 2018
Correction for Anthony et al., “Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope” journal May 2018
Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants journal April 2020
Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers journal September 2018
Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates journal June 2019
Somatic hypermutation to counter a globally rare viral immunotype drove off-track antibodies in the CAP256-VRC26 HIV-1 V2-directed bNAb lineage journal September 2019
Cooperation between somatic mutation and germline-encoded residues enables antibody recognition of HIV-1 envelope glycans journal December 2019
Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design journal August 2018
Techniques to Study Antigen-Specific B Cell Responses journal July 2019
Advances in HIV-1 Vaccine Development journal April 2018
Gp120 V5 Is Targeted by the First Wave of Sequential Neutralizing Antibodies in SHIVSF162P3N-Infected Rhesus Macaques journal May 2018
OUTRIDER: A Statistical Method for Detecting Aberrantly Expressed Genes in RNA Sequencing Data journal December 2018
HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope journal March 2018
Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection journal May 2018
Recent progress in broadly neutralizing antibodies to HIV journal October 2018
Aberrant B cell repertoire selection associated with HIV neutralizing antibody breadth journal January 2020
OUTRIDER: A statistical method for detecting aberrantly expressed genes in RNA sequencing data posted_content June 2018
Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells posted_content May 2018
An HIV-1 broadly neutralizing antibody from a clade C infected pediatric elite neutralizer potently neutralizes the contemporaneous and autologous evolving viruses posted_content August 2018
Prioritizing putatively etiological T cell epitopes across autoimmune diseases posted_content March 2019
Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases journal June 2018
Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach journal March 2018
Targeted selection of HIV-specific antibody mutations by engineering B cell maturation journal December 2019
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide journal March 2017
HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions journal January 2020
The developing premature infant gut microbiome is a major factor shaping the microbiome of neonatal intensive care unit rooms journal June 2018
Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens journal April 2019
Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells journal August 2018
HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies journal November 2018
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide text January 2017
Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies journal January 2020

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