Journal
EBIOMEDICINE
Volume 3, Issue -, Pages 122-134Publisher
ELSEVIER
DOI: 10.1016/j.ebiom.2015.12.004
Keywords
HIV-1; Envelope glycoproteins; gp120; CD4; CD4-bound conformation; Non-neutralizing antibodies; ADCC; CD4-mimetics; Bystander killing
Funding
- Canadian Institutes of Health Research [#29866, #134117, #119334, #291485] Funding Source: Medline
- NIAID NIH HHS [UM1 AI100645, UM1 AI100663, UM AI100663, NIH AI100645, P30 AI045008] Funding Source: Medline
- NIGMS NIH HHS [P01 GM056550, #GM56550] Funding Source: Medline
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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 mechanismsunderlying 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. (C) 2015 The Authors. Published by Elsevier B.V.
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