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Cell Host Microbe. 2019 Jan 9;25(1):59-72.e8. doi: 10.1016/j.chom.2018.12.001.

HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design.

Author information

1
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
2
Los Alamos National Laboratory, Los Alamos, NM 87545, USA; New Mexico Consortium, Los Alamos, NM 87545, USA.
3
Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
4
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA.
6
Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Departments of Chemistry and Biochemistry, University of Colorado, Colorado Springs, CO 80918, USA.
7
Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
8
Department of Medicine and CFAR, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
9
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA.
10
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
11
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
12
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
13
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, USA.
14
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
15
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA. Electronic address: dbarouch@bidmc.harvard.edu.
16
Los Alamos National Laboratory, Los Alamos, NM 87545, USA; New Mexico Consortium, Los Alamos, NM 87545, USA. Electronic address: btk@lanl.gov.

Abstract

Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.

KEYWORDS:

HIV-1; V2-apex antibodies; broadly neutralizing antibodies; hypervariable regions; machine learning; signature analysis; vaccine design

PMID:
30629920
PMCID:
PMC6331341
DOI:
10.1016/j.chom.2018.12.001
[Indexed for MEDLINE]
Free PMC Article

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