CD4 mimetics sensitize HIV-1-infected cells to ADCC.
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.
Richard, J; Veillette, M; Brassard, N; Iyer, SS; Roger, M; Martin, L; Pazgier, M; Schön, A; Freire, E; Routy, J-P; Smith, AB; Park, J; Jones, DM; Courter, JR; Melillo, BN; Kaufmann, DE; Hahn, BH; Permar, SR; Haynes, BF; Madani, N; Sodroski, JG; Finzi, A
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