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Cell Rep. 2017 Dec 26;21(13):3681-3690. doi: 10.1016/j.celrep.2017.12.028.

Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models.

Author information

1
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke School of Medicine, Durham, NC 27710, USA. Electronic address: kevin.saunders@duke.edu.
2
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA; Department of Pathology, Duke School of Medicine, Durham, NC 27710, USA. Electronic address: laurent.verkoczy@duke.edu.
3
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA.
4
Department of Cell Biology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
5
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
6
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke School of Medicine, Durham, NC 27710, USA.
7
Vaccine Research Center, National Institute of Allergy and Infectious Disease, Bethesda, MD 20814, USA.
8
Infectious Disease Research Institute, Seattle, WA 98102, USA.
9
Oncovir, Inc., Washington, DC 20008, USA.
10
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, Duke School of Medicine, Durham, NC 27710, USA.
11
Vaccine Research Institute (VRI), Inserm U955, Université Paris Est, AP-HP, Hôpital H. Mondor - A. Chenevier, Créteil, 94000, France.
12
Baylor Institute for Immunology Research, Dallas, TX 75204, USA; Vaccine Research Institute (VRI), Inserm U955, Université Paris Est, AP-HP, Hôpital H. Mondor - A. Chenevier, Créteil, 94000, France.
13
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke Pratt School of Engineering, Durham, NC 27710, USA.
14
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC 27710, USA; Department of Medicine and Immunology, Duke School of Medicine, Durham, NC 27710, USA. Electronic address: barton.haynes@dm.duke.edu.

Abstract

The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s. Our results show that Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate that V1V2-glycan bnAbs are more readily induced than CD4bs bnAbs, and define VH replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies.

KEYWORDS:

CH103; CH505; HIV vaccine; broadly neutralizing antibodies; knockin mice

PMID:
29281818
PMCID:
PMC5777169
DOI:
10.1016/j.celrep.2017.12.028
[Indexed for MEDLINE]
Free PMC Article

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