Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased affinity to Fcγ receptors during acute SHIVAD8-EO infection

Joana Dias, Giulia Fabozzi, Slim Fourati, Xuejun Chen, Cuiping Liu, David R. Ambrozak, Amy Ransier, Farida Laboune, Jianfei Hu, Wei Shi, Kylie March, Anna A. Maximova, Stephen D. Schmidt, Jakob Samsel, Chloe A. Talana, Keenan Ernste, Sung Hee Ko, Margaret E. Lucas, Pierce E. Radecki, Kristin L. Boswell, Yoshiaki Nishimura, John-Paul Todd, Malcolm A. Martin, Constantinos Petrovas, Eli A. Boritz, Nicole A. Doria-Rose, Daniel C. Douek, Rafick-Pierre Sékaly, Jeffrey D. Lifson, Mangaiarkarasi Asokan, Lucio Gama, John R. Mascola, Amarendra Pegu and Richard A. Koup ()
Additional contact information
Joana Dias: National Institutes of Health
Giulia Fabozzi: National Institutes of Health
Slim Fourati: Emory University
Xuejun Chen: National Institutes of Health
Cuiping Liu: National Institutes of Health
David R. Ambrozak: National Institutes of Health
Amy Ransier: National Institutes of Health
Farida Laboune: National Institutes of Health
Jianfei Hu: National Institutes of Health
Wei Shi: National Institutes of Health
Kylie March: National Institutes of Health
Anna A. Maximova: National Institutes of Health
Stephen D. Schmidt: National Institutes of Health
Jakob Samsel: National Institutes of Health
Chloe A. Talana: National Institutes of Health
Keenan Ernste: National Institutes of Health
Sung Hee Ko: National Institutes of Health
Margaret E. Lucas: National Institutes of Health
Pierce E. Radecki: National Institutes of Health
Kristin L. Boswell: National Institutes of Health
Yoshiaki Nishimura: National Institutes of Health
John-Paul Todd: National Institutes of Health
Malcolm A. Martin: National Institutes of Health
Constantinos Petrovas: National Institutes of Health
Eli A. Boritz: National Institutes of Health
Nicole A. Doria-Rose: National Institutes of Health
Daniel C. Douek: National Institutes of Health
Rafick-Pierre Sékaly: Emory University
Jeffrey D. Lifson: Frederick National Laboratory for Cancer Research
Mangaiarkarasi Asokan: National Institutes of Health
Lucio Gama: National Institutes of Health
John R. Mascola: ModeX Therapeutics
Amarendra Pegu: National Institutes of Health
Richard A. Koup: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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 SHIVAD8-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.

Date: 2024
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DOI: 10.1038/s41467-024-51848-y

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