Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir

Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure. [Display omitted] •CD4mc with CD4-induced Abs decrease the HIV-1 reservoir in SRG15-hu-mice•This treatment significantly delays viral rebound after ART interruption•This approach is dependent on Fc-effector function•CD4mc and HIV+ donor plasma suppress rebound in patient-cell-derived hu-mice Rajashekar et al. show that a small molecule CD4 mimetic, in concert with non-neutralizing antibodies, decreases the size of HIV-1 reservoir in new generation humanized mice supporting antibody and NK cell functions. Since these non-neutralizing antibodies exist in most HIV-1-infected individuals, CD4mc could translate to a functional cure strategy for HIV-AIDS.