# HIV antibodies and NK cell ADCC: nanometer-scale tracking of immune synapse dynamics.

> **NIH NIH R01** · SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE · 2023 · $492,820

## Abstract

SUMMARY
Structural studies have established that naturally elicited antibodies can bind to HIV envelope (Env) over a wide
range of epitopes and angles mediated by their Fab arm (i.e. “immune complex geometry”). How this affects
antibody dependent cellular cytotoxicity (ADCC) activity, especially by Natural Killer (NK) cells is unknown. Our
knowledge is limited by a poor understanding of how antibody immune complexes orchestrate antibody receptor
based signaling (specifically for Fc gamma RIIIa, FcRIIIa). The long-term goal is to acquire a more detailed
understanding of how antibodies recruit Fc mediated cellular activity and to develop novel strategies to engineer
antibodies, drugs, and vaccines that can recruit specific effector functions with maximal potency in vivo. The
objective of this proposal is to determine how immune complex geometry impacts NK cell ADCC against HIV
and IgG receptor spatiotemporal dynamics within the NK cell immune synapse (NKIS). Our central hypothesis
is that antibody geometry will modulate FcRIIIa interaction and ADCC activity in relation to immune complex
geometry. The rationale for this work is that cutting-edge microscopy observations will provide new insight into
ADCC function with immediate impacts on HIV antibody therapeutic design with applications to a broader range
of human diseases. Our central hypothesis will be tested in three specific aims: 1) Determine how immune
complex geometry influences FcgRIIIa interaction during ADCC; 2) Perform single molecule tracking of FcRIIIa
within the NKIS during ADCC; 3) Determine nanometer-scale localization of FcRIIIa and signaling kinases within
the NKIS during ADCC. We will pursue these aims using the innovative technique of MINFLUX nanoscopy, a
super-resolution fluorescence microscopy technique that is capable of 1- to 3-nm spatial resolutions in both 2-
and 3-dimensions as well as sub-millisecond tracking of single molecules in live cells. Carefully measured in
vitro ADCC activity and Förster resonance energy transfer (FRET) measurements will also complement our
MINFLUX observations and broaden the interpretation of our results. These studies are significant because they
will establish a molecular basis for antibody effector function, especially in relation to NK cell ADCC, that could
improve therapeutics for HIV. The techniques established in this proposal will also be useful for interrogating
antibody ADCC function for other viral pathogens. The expected outcome of our studies is the characterization
of biophysical principles that alter NK cell ADCC activity as well as the molecular mechanics that form the basis
for such activity. These findings will have an important impact on human health by offering a rational basis for
designing improved antibody therapeutics for HIV, as well as other viruses and diseases, and will increase our
basic understanding of NK cell ADCC.

## Key facts

- **NIH application ID:** 10686398
- **Project number:** 5R01AI167646-04
- **Recipient organization:** SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Charles Daniel Murin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $492,820
- **Award type:** 5
- **Project period:** 2021-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686398

## Citation

> US National Institutes of Health, RePORTER application 10686398, HIV antibodies and NK cell ADCC: nanometer-scale tracking of immune synapse dynamics. (5R01AI167646-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10686398. Licensed CC0.

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