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

TitleSmall CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity.
Publication TypeJournal Article
Year of Publication2015
AuthorsRichard J, Veillette M, Ding S, Zoubchenok D, Alsahafi N, Coutu M, Brassard N, Park J, Courter JR, Melillo B, Smith AB, Shaw GM, Hahn BH, Sodroski J, Kaufmann DE, Finzi A
JournalEBioMedicine
Volume3
Pagination122-34
Date Published12/09/2015
ISSN2352-3964
Abstract

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.

DOI10.1016/j.ebiom.2015.12.004
Alternate JournalEBioMedicine
PubMed ID26870823
PubMed Central IDPMC4739418
Grant ListUM1 AI100645 / AI / NIAID NIH HHS / United States
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