Potent and broad HIV-neutralizing antibodies in memory B cells and plasma

LaTonya D Williams; Gilad Ofek; Sebastian Schätzle; Jonathan R McDaniel; Xiaozhi Lu; Nathan I Nicely; Liming Wu; Caleb S Lougheed; Todd Bradley; Mark K Louder; Krisha McKee; Robert T Bailer; Sijy O'Dell; Ivelin S Georgiev; Michael S Seaman; Robert J Parks; Dawn J Marshall; Kara Anasti; Guang Yang; Xiaoyan Nie; Nancy L Tumba; Kevin Wiehe; Kshitij Wagh; Bette Korber; Thomas B Kepler; S Munir Alam; Lynn Morris; Gift Kamanga; Myron S Cohen; Mattia Bonsignori; Shi-Mao Xia; David C Montefiori; Garnett Kelsoe; Feng Gao; John R Mascola; M Anthony Moody; Kevin O Saunders; Hua-Xin Liao; Georgia D Tomaras; George Georgiou; Barton F Haynes

doi:10.1126/sciimmunol.aal2200

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma

Sci Immunol. 2017 Jan 27;2(7):eaal2200. doi: 10.1126/sciimmunol.aal2200.

Authors

LaTonya D Williams¹, Gilad Ofek², Sebastian Schätzle³, Jonathan R McDaniel³, Xiaozhi Lu¹, Nathan I Nicely¹, Liming Wu², Caleb S Lougheed², Todd Bradley^{1

4}, Mark K Louder⁵, Krisha McKee⁵, Robert T Bailer⁵, Sijy O'Dell⁵, Ivelin S Georgiev⁶, Michael S Seaman⁷, Robert J Parks¹, Dawn J Marshall¹, Kara Anasti¹, Guang Yang¹, Xiaoyan Nie¹, Nancy L Tumba^{8

9}, Kevin Wiehe^{1

4}, Kshitij Wagh¹⁰, Bette Korber¹⁰, Thomas B Kepler¹¹, S Munir Alam^{1

4

12}, Lynn Morris^{8

9}, Gift Kamanga¹³, Myron S Cohen¹⁴, Mattia Bonsignori^{1

4}, Shi-Mao Xia¹, David C Montefiori^{1

15}, Garnett Kelsoe^{1

16}, Feng Gao^{1

4}, John R Mascola⁵, M Anthony Moody^{1

16

17}, Kevin O Saunders^{1

15}, Hua-Xin Liao^{1

4}, Georgia D Tomaras^{1

15

16

18}, George Georgiou^{19

20}, Barton F Haynes^{21

4

16}

Affiliations

¹ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
² Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA.
³ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
⁴ Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
⁵ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, USA.
⁶ Vanderbilt Vaccine Center and Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁷ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
⁸ Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
⁹ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Congella 4013, South Africa.
¹⁰ Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
¹¹ Departments of Microbiology and Mathematics & Statistics, Boston University School of Medicine, Boston, MA 02118, USA.
¹² Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
¹³ University of North Carolina Project-Malawi, Kamuzu Central Hospital, Lilongwe, Malawi.
¹⁴ Departments of Medicine, Epidemiology, and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁵ Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
¹⁶ Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
¹⁷ Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
¹⁸ Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
¹⁹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA. barton.haynes@dm.duke.edu gg@che.utexas.edu.
²⁰ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
²¹ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. barton.haynes@dm.duke.edu gg@che.utexas.edu.

Abstract

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1-specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1-infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains.

Abstract

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