Improved killing of HIV-infected cells using three neutralizing and non-neutralizing antibodies

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Abstract

The correlation of HIV-specific antibody-dependent cellular cytotoxicity (ADCC) responses with protection from and delayed progression of HIV-1 infection provides a rationale to leverage ADCC-mediating antibodies for treatment purposes. We evaluated ADCC mediated by different combinations of 2 to 6 neutralizing and non-neutralizing anti–HIV-1 Envelope (Env) mAbs, using concentrations ≤ 1 μg/mL, to identify combinations effective at targeting latent reservoir HIV-1 viruses from 10 individuals. We found that within 2 hours, combinations of 3 mAbs mediated more than 30% killing of HIV-infected primary CD4+ T cells in the presence of autologous NK cells, with the combination of A32 (C1C2), DH511.2K3 (MPER), and PGT121 (V3) mAbs being the most effective. Increasing the incubation of target and effector cells in the presence of mAb combinations from 2 to 24 hours resulted in increased specific killing of infected cells, even with neutralization-resistant viruses. The same combination eliminated reactivated latently HIV-1–infected cells in an ex vivo quantitative viral outgrowth assay. Therefore, administration of a combination of 3 mAbs should be considered in planning in vivo studies seeking to eliminate persistently HIV-1–infected cells.

Authors

Marina Tuyishime, Carolina Garrido, Shalini Jha, Matt Moeser, Dieter Mielke, Celia LaBranche, David Montefiori, Barton F. Haynes, Sarah Joseph, David M. Margolis, Guido Ferrari