Background: Increasing evidence supports a role of Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) in controlling HIV transmission and disease progression. HIV has evolved several mechanisms to limit the recognition of ADCC-preferred Env epitopes on infected cells. We previously reported that HIV-1 uses Nef- and Vpu-mediated CD4 downregulation to efficiently reduce exposure of Env epitopes recognized by A32, a non-neutralizing, CD4-induced ADCC-competent antibody. Moreover, BST2 antagonism by Vpu limits A32 binding to gp120 on infected cells. BST2 is a type I interferon (IFN)-upregulated restriction factor that inhibits HIV-1 release by tethering nascent virions at the surface of infected cells. In this study, we hypothesized that broadly neutralizing anti-HIV antibodies (bNAbs) can also mount ADCC response and that in this context, physical tethering of virions by BST2 will promote ADCC.
Methods: Primary CD4+ T cells or T cells expressing only CD4, BST2, or both were infected with wild-type (WT) HIV or viruses deficient for Nef, Vpu or both proteins. Infected T cells were examined by flow cytometry for Env recognition by anti-HIV Env antibodies and susceptibility to ADCC.
Results: Using CD4+ T cells infected with CCR5-tropic laboratory-adapted or transmitted-founder HIV strains, we show that bNAbs efficiently induce ADCC, with those targeting the N332 glycan-V3 loop (e.g., PGT121 or PGT126) or CD4-binding site (e.g., 3BNC117) being most potent. For most bNAbs, BST2 counteraction effectively attenuates Env recognition and ADCC activity. Conversely, IFNα treatment enhances antibody binding to Env and potentiates ADCC in a BST2-dependent manner. Importantly, upon reactivation with HDAC inhibitors, latently infected T cells become potent targets of ADCC, with exogenous IFNα promoting further their elimination by bNAbs such as PGT121. Lastly, we find that modulating the levels of surface gp120 in a CD4-bound conformation, via Vpu and Nef, affects ADCC activity of only 17b, which binds the co-receptor binding site.
Conclusions: Overall, our study indicates that physical retention of HIV virions by BST2 at the cell surface sensitizes infected cells to ADCC by most classes of bNAbs. Strategies aimed at restoring the BST2 restriction represent a promising avenue to enhance clearance of latent viral reservoirs by ADCC in ʺShock and Killʺ cure approaches.