The combination of three CD4-induced antibodies targeting highly conserved Env regions with a small CD4-mimetic achieves potent ADCC activity

作者：Lorie Marchitto, Jonathan Richard, Jérémie Prévost, Alexandra Tauzin, Derek Yang, Ta-Jung Chiu, Hung-Ching Chen, Marco A. Díaz-Salinas, Manon Nayrac, Mehdi Benlarbi, Guillaume Beaudoin-Bussières, Sai Priya Anand, Katrina Dionne, Étienne Bélanger, Debashree Chatterjee, Halima Medjahed, Catherine Bourassa, William D. Tolbert, Beatrice H. Hahn, James B. Munro, Marzena Pazgier, Amos B. Smith, Andrés Finzi · 发表于：Journal of Virology · 年份：2024 · DOI：10.1128/jvi.01016-24 · 被引用次数：11 · 研究领域：Cytomegalovirus and herpesvirus research、T-cell and B-cell Immunology、HIV Research and Treatment

The majority of naturally elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs) because they are unable to recognize the Env trimer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer. HIV-1 limits this vulnerability by downregulating CD4 from the surface of infected cells, thus preventing a premature encounter of Env with CD4. Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC by opening the Env glycoprotein and exposing CD4-induced (CD4i) epitopes. There are two families of CD4i nnAbs, termed anti-cluster A and anti-CoRBS Abs, which are known to mediate ADCC in the presence of CD4mc. Here, we performed Fab competition experiments and found that anti-gp41 cluster I antibodies comprise a major fraction of the plasma ADCC activity in people living with HIV (PLWH). Moreover, addition of gp41 cluster I antibodies to cluster A and CoRBS antibodies greatly enhanced ADCC-mediated cell killing in the presence of a potent indoline CD4mc, CJF-III-288. This cocktail outperformed broadly neutralizing antibodies and even showed activity against HIV...