期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 20, 页码 E2687-E2694出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1506755112
关键词
HIV-1; envelope glycoproteins; gp120; CD4 mimetics; ADCC
资金
- Canada Foundation
- Canadian Institutes of Health Research operating [119334, 134117]
- Fonds de Recherche Quebec Sante Establishment of Young Scientist [26702]
- FRQS AIDS and Infectious Diseases Network
- CIHR Doctoral Research Award [291485]
- CIHR Fellowship Award [135349]
- Research Scholar Career Award of the Quebec Health Research Fund [25131]
- NIH [R01AI111789, R01AI114266, R01AI087181, R01HL092565, P30AI045008, GM56550, AI100645, UM1AI24755, UM1AI100663, AI106380, AI090682]
- International AIDS Vaccine Initiative
- Bill and Melinda Gates Foundation [OPP1033109]
- National Science Foundation [MCB-1157506]
- amfAR [107431-45-RFNT]
- Ragon Institute Innovation Award
HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.
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