Journal
AIDS
Volume 29, Issue 14, Pages 1767-1773Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000000777
Keywords
AIDS; cytotoxicity; interferon-alpha; NK cells; NKG2D; NKp46
Categories
Funding
- National Institutes of Health [AI51225, AI47760, U01AI065279, AI07632, AI068405]
- Philadelphia Foundation
- Commonwealth Universal Research Enhancement Program
- Pennsylvania Department of Health the Italian Ministry of Health (Ricerca Finalizzata, Bando ISS) [RF-ICH-2009-1299677, RF-ICH-2009-1304134]
- Cancer Center Support Grant (CCSG) [P30CA010815]
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Objective: Autologous HIV-1-infected CD4(+) primary T cells (aHIV(+)CD4) have been shown to be largely resistant to natural killer (NK)-cell-mediated lysis because of viral strategies of immune evasion. We have previously shown that a preactivation of NK cells with plasmacytoid dendritic cells can significantly augment lysis of aHIV(+)CD4 through a mechanism dependent on interferon-alpha (IFN-alpha). Design: The goal of the present study is to identify the specific NK-activating receptors involved in NK lysis of aHIV(+)CD4 following IFN-alpha activation. Methods: Peripheral blood mononuclear cells (PBMC) were incubated with aHIV(+)CD4 to induce the secretion of endogenous levels of IFN-alpha and drive NK activation. We then utilized a standard chromium lysis assay to assess the degree of IFN-alpha-activated lysis of aHIV(+)CD4 in the presence or absence of masking antibodies to a panel of NK-activating receptors and co-receptors. Results: Direct recognition of HIV-1-infected, but not uninfected, autologous CD4(+) primary T cells by PBMC induced the secretion IFN-alpha (median 2280pg/ml, P < 0.001, n = 9) that, in turn, activated NK cells (P < 0.001, n = 12) and significantly increased their cytolytic potential against aHIV(+)CD4 (P < 0.01, n=12). The masking of NKp46 (P < 0.01, n = 8) and NKG2D (P < 0.05, n = 8), but not 2B4, NTBA, NKp30 or NKp44, significantly reduced IFN-alpha-activated lysis of aHIV(+)CD4. Conclusions: Taken together, these results demonstrate that endogenous levels of IFN- secreted by plasmacytoid dendritic cells induce NK cells to lyse aHIV(+)CD4 via the engagement of NKp46 and NKG2D. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.
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