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

• Published in: The Journal of clinical investigation 2020-10, Vol.130 (10), p.5157-5170
• Main Authors: Tuyishime, Marina, Garrido, Carolina, Jha, Shalini, Moeser, Matt, Mielke, Dieter, LaBranche, Celia, Montefiori, David, Haynes, Barton F, Joseph, Sarah, Margolis, David M, Ferrari, Guido
• Format: Article
• Language: English
• Subjects: Adult; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - immunology; Antibody-Dependent Cell Cytotoxicity - immunology; Antiviral agents; Biomedical research; Broadly Neutralizing Antibodies - administration & dosage; Broadly Neutralizing Antibodies - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cytotoxicity; Development and progression; Disease Reservoirs - virology; Effector cells; Female; Health aspects; HIV; HIV Antibodies - administration & dosage; HIV Antibodies - immunology; HIV infections; HIV Infections - immunology; HIV Infections - therapy; HIV patients; HIV-1 - immunology; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunotherapy - methods; In Vitro Techniques; Infection; Infections; Killer cells; Killer Cells, Natural - immunology; Kinetics; Lymphocytes; Lymphocytes T; Male; Middle Aged; Monoclonal antibodies; Neutralization Tests; T cells; Viral infections; Virus Latency - immunology; Viruses
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI135557

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.