HIV-1 Vpu restricts Fc-mediated effector functions in vivo

Jérémie Prévost; Sai Priya Anand; Jyothi Krishnaswamy Rajashekar; Li Zhu; Jonathan Richard; Guillaume Goyette; Halima Medjahed; Gabrielle Gendron-Lepage; Hung-Ching Chen; Yaozong Chen; Joshua A Horwitz; Michael W Grunst; Susan Zolla-Pazner; Barton F Haynes; Dennis R Burton; Richard A Flavell; Frank Kirchhoff; Beatrice H Hahn; Amos B Smith 3rd; Marzena Pazgier; Michel C Nussenzweig; Priti Kumar; Andrés Finzi

doi:10.1016/j.celrep.2022.111624

HIV-1 Vpu restricts Fc-mediated effector functions in vivo

Cell Rep. 2022 Nov 8;41(6):111624. doi: 10.1016/j.celrep.2022.111624.

Authors

Jérémie Prévost¹, Sai Priya Anand², Jyothi Krishnaswamy Rajashekar³, Li Zhu³, Jonathan Richard⁴, Guillaume Goyette⁵, Halima Medjahed⁵, Gabrielle Gendron-Lepage⁵, Hung-Ching Chen⁶, Yaozong Chen⁷, Joshua A Horwitz⁸, Michael W Grunst³, Susan Zolla-Pazner⁹, Barton F Haynes¹⁰, Dennis R Burton¹¹, Richard A Flavell¹², Frank Kirchhoff¹³, Beatrice H Hahn¹⁴, Amos B Smith 3rd⁶, Marzena Pazgier⁷, Michel C Nussenzweig⁸, Priti Kumar³, Andrés Finzi¹⁵

Affiliations

¹ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada. Electronic address: jeremie.prevost@umontreal.ca.
² Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
³ Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06510, USA.
⁴ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada.
⁵ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada.
⁶ Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
⁷ Infectious Diseases Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.
⁸ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
⁹ Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰ Duke Human Vaccine Institute, Departments of Medicine and Immunology, Duke University School of Medicine, Durham, NC 27710, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), Duke University, Durham, NC 27710, USA.
¹¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard University, Cambridge, MA 02139, USA.
¹² Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
¹³ Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
¹⁴ Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
¹⁵ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: andres.finzi@umontreal.ca.

Abstract

Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to "open" Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.

Keywords: ADCC; CD4 mimetics; CP: Immunology; Env; Fc-effector functions; HIV-1; Vpu; broadly neutralizing antibodies; humanized mice; immune evasion; non-neutralizing antibodies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing
Antibody-Dependent Cell Cytotoxicity
HIV Antibodies
HIV Infections*
HIV Seropositivity*
HIV-1*
Humans
Mice

Substances

Antibodies, Neutralizing
HIV Antibodies

Abstract

Publication types

MeSH terms

Substances

Grants and funding