Abstract
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.
Highlights
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)
Env-CD4 interaction is modulated by the HIV-1 accessory proteins Nef and Vpu, which are known to decrease cell surface levels of CD4 [29, 30]
Cells infected with viruses defective for both Nef and Vpu present enhanced levels of CD4 and Env at the cell surface, resulting in the exposure of CD4i Env epitopes recognized by ADCC-mediating Abs such as A32 and HIV-1+ sera [11, 12] (Fig. 1 A and B)
Summary
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). | envelope glycoproteins | gp120 | CD4 mimetics | ADCC surface of HIV-1-infected cells has become feasible as a result of the availability of small CD4-mimetic compounds (CD4mc) The prototypes of such compounds, NBD-556 and NBD-557, were discovered in a screen for inhibitors of gp120-CD4 interaction [19]. CD4mc block gp120-CD4 interaction and induce thermodynamic changes in gp120 similar to those observed during CD4 or soluble CD4 (sCD4) binding [24] These small molecules, as well as sCD4, can promote the transition of Env to the CD4-bound conformation, sensitizing HIV-1 particles to neutralization by otherwise nonneutralizing CD4i Abs [17, 25]. We and others reported that Env in the CD4-bound conformation was preferentially targeted by ADCC-mediating Abs and sera from HIV-1-infected individuals [11, 12, 15, 16], which represent a significant proportion of anti-Env Abs elicited during natural
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