BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity.
Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-β and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals.IMPORTANCEHIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-β and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication.
Centre de Recherche du CHUM, Montreal, Quebec, Canada jonathan.richard.1@umontreal.ca andres.finzi@umontreal.ca.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
Jonathan
J
Richard
Centre de Recherche du CHUM, Montreal, Quebec, Canada.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
Jérémie
J
Prévost
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Benjamin
B
von Bredow
Centre de Recherche du CHUM, Montreal, Quebec, Canada.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
Shilei
S
Ding
Centre de Recherche du CHUM, Montreal, Quebec, Canada.
Nathalie
N
Brassard
Centre de Recherche du CHUM, Montreal, Quebec, Canada.
Halima
H
Medjahed
Centre de Recherche du CHUM, Montreal, Quebec, Canada.
Mathieu
M
Coutu
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Bruno
B
Melillo
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Frédéric
F
Bibollet-Ruche
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Beatrice H
BH
Hahn
Centre de Recherche du CHUM, Montreal, Quebec, Canada.|Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA.
Daniel E
DE
Kaufmann
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Amos B
AB
Smith
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Division of AIDS, Harvard Medical School, Boston, Massachusetts, USA.|Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
Joseph
J
Sodroski
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Daniel
D
Sauter
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Frank
F
Kirchhoff
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Katrina
K
Gee
Department of Infectious Disease, King's College London School of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom.
Stuart J
SJ
Neil
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
David T
DT
Evans
Centre de Recherche du CHUM, Montreal, Quebec, Canada jonathan.richard.1@umontreal.ca andres.finzi@umontreal.ca.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Andrés
A
Finzi
D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D016899:Interferon-beta / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D019169:Jurkat Cells; D018716:Molecular Mimicry; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D015703:Antigens, CD; D015704:CD4 Antigens; D000939:Epitopes; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D016899:Interferon-beta; D007378:Interleukins; D054334:Viral Regulatory and Accessory Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C464565:MYDGF protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
ADCC; BST-2; CD4; CD4 mimetics; CD4-bound conformation; Env; HIV-1; IFN-α; IL-27; envelope glycoproteins; gp120; interferons; nonneutralizing antibodies