Envelope Glycoprotein Internalization Protects Human and Simian Immunodeficiency Virus-Infected Cells from Antibody-Dependent Cell-Mediated Cytotoxicity

Benjamin von Bredow; Juan F. Arias; Lisa N. Heyer; Matthew R. Gardner; Michael Farzan; Eva G. Rakasz; David T. Evans

doi:10.1128/JVI.01911-15

Envelope Glycoprotein Internalization Protects Human and Simian Immunodeficiency Virus-Infected Cells from Antibody-Dependent Cell-Mediated Cytotoxicity

^aDepartment of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Madison, Wisconsin, USA
^bNew England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA
^cDepartment of Infectious Disease, The Scripps Research Institute, Jupiter, Florida, USA
^dWisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, USA

F. Kirchhoff, Editor

ABSTRACT

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.

IMPORTANCE 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.

FOOTNOTES

Received 29 July 2015.
Accepted 4 August 2015.
Accepted manuscript posted online 12 August 2015.

Address correspondence to David T. Evans, dtevans2{at}wisc.edu.
Citation von Bredow B, Arias JF, Heyer LN, Gardner MR, Farzan M, Rakasz EG, Evans DT. 2015. Envelope glycoprotein internalization protects human and simian immunodeficiency virus-infected cells from antibody-dependent cell-mediated cytotoxicity. J Virol 89:10648–10655. doi:10.1128/JVI.01911-15.