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.

Automated summary

Research has shown that CD4mc can sensitize HIV-1-infected cells to ADCC by facilitating antibody recognition of epitopes on the viral envelope that are otherwise occluded. Combining CD4mc with specific antibodies can reduce viral replication and reservoir size by enhancing ADCC. The dependence on NK cells and Fc effector functions for these effects highlights the importance of ADCC in combating HIV-1.