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.
| Original language | English (US) |
|---|---|
| Article number | 7461 |
| Journal | Nature communications |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
This work was supported by the Bill and Melinda Gates Foundation (Grant OPP1147555 to R.A.K) and by the Intramural Research Program of the VRC, NIAID, NIH, and in part with federal funds from the National Cancer Institute, NIH, under Contract No. 75N91019D00024/HHSN261201500003I (J.D.L). We thank Saran Bao, Jumagul Noor, John Graves, Caitlyn Miller, Alida Taylor, Hana Bao, Elizabeth McCarthy, Diana Scorpio, and Ruth Woodward from the Translational Research Program, VRC, for help with the animal experiments; Amy Noe, Shing-Fen Kao, Nadesh Nji, Dillon Flebbe, Evan Lamb, and Kathryn Foulds from the NHP Immunogenicity Core, VRC, for processing some NHP samples; Jesmine Roberts-Torres from the Human Immunology Section, VRC, for helping process samples for transcriptomic analyses; Richard Nguyen, Esther Thang, Daniela Ischiu Gutierrez, Erica Smit, and Steve Perfetto from the Flow Cytometry Core, VRC, for assistance with the flow cytometers; Wanwisa Promsote from the Immunology Laboratory, VRC, for sharing the flow cytometry panel for whole blood cell count, and Christopher Gonelli, Joseph Casazza, and Rodrigo Matus-Nicodemos from the Immunology Laboratory, VRC, for helpful scientific suggestions and discussions. We also thank Kevin Carlton and the staff of the Vaccine Production Program, VRC, for manufacturing some of the bNAbs used in monkey infusions and ELISAs; Baoshan Zhang from the Structural Biology Section, VRC, for providing the 3BNC117 bNAb for neutralization assays, and Krisha McKee from the Humoral Immunology Section, VRC, for help with neutralization data analysis. We are also thankful to Martha Nason from the Biostatistics Research Branch, NIAID, NIH, for expert statistical advice; Reza Sadjadpour from the Laboratory of Molecular Microbiology, NIAID, NIH, for assistance with SHIVAD8-EO Env sequencing data analysis; the staff of the Quantitative Molecular Diagnostics Core of the AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, for measurements of plasma viral load and cell-associated viral nucleic acids; and Matthew Gastinger from Imaris, an Oxford Instruments Company, for expert advice in imaging analyses. The anti-CD8\u03B2 mAb CD8b255R1 used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116).
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
