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Cell Rep. 2016 Jan 5;14(1):43-54. doi: 10.1016/j.celrep.2015.12.017. Epub 2015 Dec 24.

Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site.

Author information

1
Duke Human Vaccine Institute, Departments of Medicine, Surgery and Immunology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: todd.bradley@duke.edu.
2
Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
National Institute for Communicable Diseases, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2131, South Africa.
4
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
5
Duke Human Vaccine Institute, Departments of Medicine, Surgery and Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
6
Center for AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa; Columbia University, New York, NY 10032, USA.
7
Novartis Vaccines and Diagnostics, Inc., Cambridge, MA 02139, USA.
8
Boston University, Boston, MA 02118, USA.
9
National Institute for Communicable Diseases, Johannesburg 2131, South Africa; Center for AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban 4013, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2131, South Africa.
10
Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA.
11
Duke Human Vaccine Institute, Departments of Medicine, Surgery and Immunology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: barton.haynes@duke.edu.

Abstract

Antibodies that neutralize autologous transmitted/founder (TF) HIV occur in most HIV-infected individuals and can evolve to neutralization breadth. Autologous neutralizing antibodies (nAbs) against neutralization-resistant (Tier-2) viruses are rarely induced by vaccination. Whereas broadly neutralizing antibody (bnAb)-HIV-Envelope structures have been defined, the structures of autologous nAbs have not. Here, we show that immunization with TF mutant Envs gp140 oligomers induced high-titer, V5-dependent plasma neutralization for a Tier-2 autologous TF evolved mutant virus. Structural analysis of autologous nAb DH427 revealed binding to V5, demonstrating the source of narrow nAb specificity and explaining the failure to acquire breadth. Thus, oligomeric TF Envs can elicit autologous nAbs to Tier-2 HIVs, but induction of bnAbs will require targeting of precursors of B cell lineages that can mature to heterologous neutralization.

PMID:
26725118
PMCID:
PMC4706810
DOI:
10.1016/j.celrep.2015.12.017
[Indexed for MEDLINE]
Free PMC Article

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