Richard, JonathanVeillette, MaximeDing, ShileiZoubchenok, DariaAlsahafi, NirminCoutu, MathieuBrassard, NathaliePark, JongwooCourter, Joel R.Melillo, BrunoSmith, Amos B.Shaw, George M.Hahn, Beatrice H.Sodroski, JosephKaufmann, Daniel E.Finzi, Andrés2016-03-012015Richard, J., M. Veillette, S. Ding, D. Zoubchenok, N. Alsahafi, M. Coutu, N. Brassard, et al. 2015. “Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity.” EBioMedicine 3 (1): 122-134. doi:10.1016/j.ebiom.2015.12.004. http://dx.doi.org/10.1016/j.ebiom.2015.12.004.2352-3964http://nrs.harvard.edu/urn-3:HUL.InstRepos:25658535Human 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.en-USHIV-1Envelope glycoproteinsgp120CD4CD4-bound conformationNon-neutralizing antibodiesADCCCD4-mimeticsBystander killingJournal Article2016-03-0110.1016/j.ebiom.2015.12.004