Prevention of HIV-1 transmission and progression likely requires approaches that can specifically eliminate HIV-1-infected cells. There is increasing evidence supporting a role of Antibody-Dependent Cell- Mediated Cytotoxicity (ADCC) in controlling HIV-1 transmission and disease progression. However, Env epitopes targeted by antibodies effective at mediating ADCC are poorly exposed on the unliganded[LINE SEPARATOR]HIV-1 envelope glycoprotein (Env) trimer. Indeed, HIV-1 has evolved[LINE SEPARATOR]a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by downregulating CD4 and by limiting the amount of Env at the cell surface. We observed that interaction of Env with the CD4 receptor was required for efficient exposure of ADCC-mediating Env epitopes. In that context, HIV-1-infected cells presenting HIV-1 Env in the CD4-bound conformation on their surface were found to be preferentially targeted by ADCC-mediating antibodies present in sera of HIV-1-infected individuals. We therefore tested the capacity of rationally-designed CD4-mimetic compounds (CD4mc) to promote the CD4-bound conformation of Env and thereby sensitize HIV-1-infected cells to ADCC. We observed that certain CD4mc induce the CD4-bound conformation of Env and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by easy-to- elicit antibodies present in sera from early converters and chronically- infected individuals. Importantly, CD4mc also enhanced recognition[LINE SEPARATOR]and ADCC-mediated elimination of HIV-1-infected cells by antibodies present in breast milk and cervico-vaginal lavages of HIV-1-infected women. Finally, we identified one CD4mc with the capacity to sensitize endogenously-infected ex-vivo-amplified primary CD4 T cells to ADCC mediated by autologous sera and effector cells. By pushing Env into the CD4-bound conformation, CD4mc might represent an alternative and/or complementary approach to currently-available drugs for preventing viral transmission and might be helpful for eradication strategies.
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