Abstract
Antibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env) trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8). Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1) can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2) exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10–1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells.
Highlights
Natural killer (NK) cells and other Fc-gamma receptor (FcγR)-expressing cells can eliminate HIV-1 infected cells through antibody-dependent cell-mediated cytotoxicity (ADCC) [1,2,3]
We demonstrate the unique properties of eCD4-Ig, a potent and exceptionally broad antibody-like HIV-1 entry inhibitor
Unlike most antibodies, eCD4-Ig can promote envelope glycoprotein (Env) conformational changes that allow abundant but otherwise inert antibodies in patient sera to mediate killing of infected cells. This property may be especially useful in efforts to cure HIV-1 by reactivating virus in latently infected cells and killing these virus-producing cells
Summary
Natural killer (NK) cells and other Fc-gamma receptor (FcγR)-expressing cells can eliminate HIV-1 infected cells through antibody-dependent cell-mediated cytotoxicity (ADCC) [1,2,3]. These ADCC activities depend on the antibody isotype [4,5]. Growing evidence suggests that ADCC is an important component of protective immune responses against HIV-1 infection [1,2,6,7,8]. Studies of passively administered antibodies in animal models have suggested that ADCC contributes to protection from simian-human immunodeficiency viruses (SHIV) [10]. Efforts are underway to reduce the viral reservoir by combining latency-reversing agents, which stimulate virion production in latently infected cells, with antibodies that may accelerate elimination of these cells [12,13]
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