Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4+ T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity

EBioMedicine

Maxime Veillette¹  Daniel E. Kaufmann¹  Mathieu Coutu¹  Nathalie Brassard¹  Andrés Finzi¹  Daria Zoubchenok¹  Shilei Ding¹  Nirmin Alsahafi¹  Jonathan Richard¹  Joseph Sodroski²  Amos B. Smith III³  Bruno Melillo³  Jongwoo Park³  Joel R. Courter³  George M. Shaw⁴  Beatrice H. Hahn⁴ 

[1] Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada;Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA;Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA;Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA;

关键词: HIV-1;    Envelope glycoproteins;    gp120;    CD4;    CD4-bound conformation;    Non-neutralizing antibodies;    ADCC;    CD4-mimetics;    Bystander killing;   

DOI  :  10.1016/j.ebiom.2015.12.004

来源: DOAJ

【 摘 要 】

Human immunodeficiency virus type 1 (HIV-1) infection causes a progressive depletion of CD4+ T cells. Despite its importance for HIV-1 pathogenesis, the precise mechanisms underlying CD4+ T-cell depletion remain incompletely understood. Here we make the surprising observation that antibody-dependent cell-mediated cytotoxicity (ADCC) mediates the death of uninfected bystander CD4+ T cells in cultures of HIV-1-infected cells. While HIV-1-infected cells are protected from ADCC by the action of the viral Vpu and Nef proteins, uninfected bystander CD4+T cells bind gp120 shed from productively infected cells and are efficiently recognized by ADCC-mediating antibodies. Thus, gp120 shedding represents a viral mechanism to divert ADCC responses towards uninfected bystander CD4+ T cells. Importantly, CD4-mimetic molecules redirect ADCC responses from uninfected bystander cells to HIV-1-infected cells; therefore, CD4-mimetic compounds might have therapeutic utility in new strategies aimed at specifically eliminating HIV-1-infected cells.

【 授权许可】

Unknown