Envelope Glycoprotein Internalization Protects Human and Simian Immunodeficiency Virus-Infected Cells from Antibody-Dependent Cell-Mediated Cytotoxicity.
The cytoplasmic tails of human and simian immunodeficiency virus (HIV and SIV, respectively) envelope glycoproteins contain a highly conserved, membrane-proximal endocytosis motif that prevents the accumulation of Env on the surface of infected cells prior to virus assembly. Using an assay designed to measure the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC), we show that substitutions in this motif increase the susceptibility of HIV-1- and SIV-infected cells to ADCC in a manner that directly correlates with elevated Env levels on the surface of virus-infected cells. In the case of HIV-1, this effect is additive with a deletion in vpu recently shown to enhance the susceptibility of HIV-1-infected cells to ADCC as a result of tetherin-mediated retention of budding virions on the cell surface. These results reveal a previously unappreciated role for the membrane-proximal endocytosis motif of gp41 in protecting HIV-1- and SIV-infected cells from antibody responses by regulating the amount of Env present on the cell surface.


OBJECTIVE
This study reveals an unappreciated role for the membrane-proximal endocytosis motif of gp41 in protecting HIV-1- and SIV-infected cells from elimination by Env-specific antibodies. Thus, strategies designed to interfere with this mechanism of Env internalization may improve the efficacy of antibody-based vaccines and antiretroviral therapies designed to enhance the immunological control of HIV-1 replication in chronically infected individuals.
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Madison, Wisconsin, USA.
Benjamin
B
von Bredow
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Madison, Wisconsin, USA.
Juan F
JF
Arias
New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
Lisa N
LN
Heyer
Department of Infectious Disease, The Scripps Research Institute, Jupiter, Florida, USA.
Matthew R
MR
Gardner
Department of Infectious Disease, The Scripps Research Institute, Jupiter, Florida, USA.
Michael
M
Farzan
Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, USA.
Eva G
EG
Rakasz
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Madison, Wisconsin, USA Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, USA dtevans2@wisc.edu.
David T
DT
Evans
D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000235:genetics; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000276:immunology / Q000821:virology; D017124:Conserved Sequence; D004705:Endocytosis / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D000914:Antibodies, Viral; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D015700:HIV Envelope Protein gp41; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514787:gp41 protein, Human immunodeficiency virus 1; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins