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

Todd Bradley; Daniela Fera; Jinal Bhiman; Leila Eslamizar; Xiaozhi Lu; Kara Anasti; Ruijung Zhang; Laura L Sutherland; Richard M Scearce; Cindy M Bowman; Christina Stolarchuk; Krissey E Lloyd; Robert Parks; Amanda Eaton; Andrew Foulger; Xiaoyan Nie; Salim S Abdool Karim; Susan Barnett; Garnett Kelsoe; Thomas B Kepler; S Munir Alam; David C Montefiori; M Anthony Moody; Hua-Xin Liao; Lynn Morris; Sampa Santra; Stephen C Harrison; Barton F Haynes

doi:10.1016/j.celrep.2015.12.017

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

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

Authors

Todd Bradley¹, Daniela Fera², Jinal Bhiman³, Leila Eslamizar⁴, Xiaozhi Lu⁵, Kara Anasti⁵, Ruijung Zhang⁵, Laura L Sutherland⁵, Richard M Scearce⁵, Cindy M Bowman⁵, Christina Stolarchuk⁵, Krissey E Lloyd⁵, Robert Parks⁵, Amanda Eaton⁵, Andrew Foulger⁵, Xiaoyan Nie⁵, Salim S Abdool Karim⁶, Susan Barnett⁷, Garnett Kelsoe⁵, Thomas B Kepler⁸, S Munir Alam⁵, David C Montefiori⁵, M Anthony Moody⁵, Hua-Xin Liao⁵, Lynn Morris⁹, Sampa Santra⁴, Stephen C Harrison¹⁰, Barton F Haynes¹¹

Affiliations

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.

MeSH terms

AIDS Vaccines* / immunology
AIDS Vaccines* / pharmacology
Amino Acid Sequence
Animals
Antibodies, Neutralizing / immunology*
Female
HIV Antibodies / immunology*
HIV-1* / genetics
HIV-1* / immunology
Humans
Macaca mulatta
Male
Molecular Sequence Data
env Gene Products, Human Immunodeficiency Virus* / genetics
env Gene Products, Human Immunodeficiency Virus* / immunology

Substances

AIDS Vaccines
Antibodies, Neutralizing
HIV Antibodies
env Gene Products, Human Immunodeficiency Virus
gp140 envelope protein, Human immunodeficiency virus 1

Grants and funding

UM1 AI100645/AI/NIAID NIH HHS/United States