1. Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased affinity to Fcγ receptors during acute SHIV AD8-EO infection.
- Author
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Dias J, Fabozzi G, Fourati S, Chen X, Liu C, Ambrozak DR, Ransier A, Laboune F, Hu J, Shi W, March K, Maximova AA, Schmidt SD, Samsel J, Talana CA, Ernste K, Ko SH, Lucas ME, Radecki PE, Boswell KL, Nishimura Y, Todd JP, Martin MA, Petrovas C, Boritz EA, Doria-Rose NA, Douek DC, Sékaly RP, Lifson JD, Asokan M, Gama L, Mascola JR, Pegu A, and Koup RA
- Subjects
- Animals, Antibodies, Monoclonal immunology, Lymph Nodes immunology, CD8-Positive T-Lymphocytes immunology, Antibody Affinity immunology, NF-kappa B metabolism, NF-kappa B immunology, Humans, HIV Infections immunology, HIV Infections virology, Killer Cells, Natural immunology, Broadly Neutralizing Antibodies immunology, Receptors, IgG immunology, Receptors, IgG metabolism, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, HIV-1 immunology, Simian Immunodeficiency Virus immunology, Macaca mulatta, Antibodies, Neutralizing immunology, HIV Antibodies immunology
- Abstract
Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIV
AD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8+ CD69+ T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2024
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