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Title: HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope

Abstract

HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide (“Man9-V3”) for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage (“DH270”), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs—the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.

Authors:
ORCiD logo [1];  [1];  [2];  [3]; ORCiD logo [1];  [2];  [4];  [4];  [5];  [5];  [4];  [2];  [1]
  1. Harvard Medical School, Boston, MA (United States)
  2. Duke Univ. Medical Center, Durham, NC (United States); Duke Human Vaccine Inst., Durham, NC (United States)
  3. Duke Human Vaccine Inst., Durham, NC (United States); Duke Univ. Medical Center, Durham, NC (United States)
  4. Sloan Kettering Institute, New York, NY (United States)
  5. Swarthmore College, PA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; National Institutes of Health (NIH); NIH-ORIP HEI; National Inst. of Allergy and Infectious Diseases; Medical Scientist Training Program (MSTP)
OSTI Identifier:
1431358
Grant/Contract Number:  
AC02-06CH11357; P41 GM103403; S10 RR029205; AI100645; T32GM007171; Al127193
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Antibodies; HIV infections; Structural biology; Vaccines

Citation Formats

Fera, Daniela, Lee, Matthew S., Wiehe, Kevin, Meyerhoff, R. Ryan, Piai, Alessandro, Bonsignori, Mattia, Aussedat, Baptiste, Walkowicz, William E., Ton, Therese, Zhou, Jeffrey O., Danishefsky, Samuel, Haynes, Barton F., and Harrison, Stephen C. HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope. United States: N. p., 2018. Web. doi:10.1038/s41467-018-03565-6.
Fera, Daniela, Lee, Matthew S., Wiehe, Kevin, Meyerhoff, R. Ryan, Piai, Alessandro, Bonsignori, Mattia, Aussedat, Baptiste, Walkowicz, William E., Ton, Therese, Zhou, Jeffrey O., Danishefsky, Samuel, Haynes, Barton F., & Harrison, Stephen C. HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope. United States. doi:10.1038/s41467-018-03565-6.
Fera, Daniela, Lee, Matthew S., Wiehe, Kevin, Meyerhoff, R. Ryan, Piai, Alessandro, Bonsignori, Mattia, Aussedat, Baptiste, Walkowicz, William E., Ton, Therese, Zhou, Jeffrey O., Danishefsky, Samuel, Haynes, Barton F., and Harrison, Stephen C. Fri . "HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope". United States. doi:10.1038/s41467-018-03565-6. https://www.osti.gov/servlets/purl/1431358.
@article{osti_1431358,
title = {HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope},
author = {Fera, Daniela and Lee, Matthew S. and Wiehe, Kevin and Meyerhoff, R. Ryan and Piai, Alessandro and Bonsignori, Mattia and Aussedat, Baptiste and Walkowicz, William E. and Ton, Therese and Zhou, Jeffrey O. and Danishefsky, Samuel and Haynes, Barton F. and Harrison, Stephen C.},
abstractNote = {HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide (“Man9-V3”) for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage (“DH270”), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs—the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.},
doi = {10.1038/s41467-018-03565-6},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {3}
}

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    Works referencing / citing this record:

    Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers
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