CD4 mimetics sensitize HIV-1-infected cells to ADCC

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 20; pp. E2687 - E2694
• Main Authors: Richard, Jonathan, Veillette, Maxime, Brassard, Nathalie, Iyer, Shilpa S., Roger, Michel, Martin, Loïc, Pazgier, Marzena, Schön, Arne, Freire, Ernesto, Routy, Jean-Pierre, Smith, Amos B., Park, Jongwoo, Jones, David M., Courter, Joel R., Melillo, Bruno N., Kaufmann, Daniel E., Hahn, Beatrice H., Permar, Sallie R., Haynes, Barton F., Madani, Navid, Sodroski, Joseph G., Finzi, Andrés
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.05.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Antibody-Dependent Cell Cytotoxicity - immunology; Biochemistry; Biochemistry, Molecular Biology; Biological Sciences; Breastfeeding & lactation; CD4 Antigens - immunology; CD4 Antigens - metabolism; CD4-Positive T-Lymphocytes - immunology; Cells; Chemical Sciences; Cytotoxicity; env Gene Products, Human Immunodeficiency Virus - metabolism; Flow Cytometry; Glycoproteins; HEK293 Cells; HIV; HIV Infections - prevention & control; HIV Infections - transmission; HIV-1 - immunology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immunology; Immunotherapy; Life Sciences; Medicinal Chemistry; Molecules; Mutagenesis, Site-Directed; PNAS Plus; Protein Conformation; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; Vaccinology; HIV-1; gp120; CD4 mimetics; ADCC; envelope glycoproteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1506755112

Significance The prevention of HIV-1 transmission and progression likely requires approaches that can specifically eliminate HIV-1-infected cells. Rationally designed CD4-mimetic compounds (CD4mc) have been shown to efficiently inhibit viral entry and sensitize HIV-1 particles to neutralization by otherwise nonneutralizing CD4-induced antibodies. Here we found that CD4mc can also sensitize HIV-1-infected cells to antibody-dependent cell-mediated cytotoxicity (ADCC). Indeed, CD4mc induced the CD4-bound conformation of HIV-1 envelope glycoproteins, exposing CD4-induced epitopes recognized by easy-to-elicit antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we provide evidence that CD4mc can efficiently sensitize primary CD4 T cells from HIV-1-infected individuals to ADCC mediated by autologous sera and effector cells. Therefore, CD4mc might represent an attractive approach to prevent and control HIV-1 infection. 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.