# In vivo transformation of chimeric antigen receptor B cells for a functional cure of HIV

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $824,985

## Abstract

PROJECT SUMMARY
Our laboratories have developed novel techniques for the editing B-cell receptors of human primary B cells.
Using newly identified CRISPR/Cas proteins and innovative homology-directed repair templates, we can
efficiently overwrite the endogenous variable heavy (VH) and variable light (VL) segments of a mature VDJ-
recombined BCR with the variable genes of broadly neutralizing HIV antibodies (bNabs). Importantly, these
variable genes are placed in their respective natural loci, and – excepting the new VH and VL segments –
these edited B cells are indistinguishable from unmodified mature, naïve B cells. We describe these edited B
cells as “chimeric antigen receptor B cells”, or CAR B cells, evoking the more familiar CAR T cells.
These CAR B cells replicate, differentiate, affinity mature, and secrete antibodies in vivo providing an efficient
delivery vehicle for bNabs. CAR B cells represent a key advance over passive infusion or gene therapy
delivery of bNabs, because they do not raise anti-drug antibodies against their novel BCR, and because the
can affinity mature in response to an antigen, including HIV-1 emerging from a reactivated reservoir. They
can thus adapt in real time to the specific viral variants in the reservoir.
To date, however, we have only transformed CAR B cells ex vivo by isolating primary B cells from a particular
host, transforming them by electroporation of CRISPR/Cas RNPs and DNA repair templates, and re-infusing
the CAR B cells into the host. Although ex vivo CAR B transformation could be clinically viable, it would likely
be a prohibitively expensive procedure for most HIV-positive persons. Here we propose to perform the CAR
B transformation procedure in vivo by developing a B cell-tropic adeno-associated virus (AAV)-based gene
therapy vector and CRISPS/Cas editing cassette that could be administered intravenously; a comparatively
fast and inexpensive procedure.
This proposal is divided into three aims. In Aim 1, we draw upon our extensive experience modifying AAV
capsids to target specific cell types to create a B cell-tropic capsid. In Aim 2, we develop and evaluate a range
of AAV-delivered CRISPR/Cas editing cassette designs for their ability to efficiently transform CAR B cells.
Lastly, in Aim 3, we optimize an immunogen and immunization strategy to drive proliferation and affinity
maturation of newly transformed CAR B cells. These studies will make clinically viable a promising approach
for suppressing an established HIV-1 infection or preventing a new one in high-risk persons.

## Key facts

- **NIH application ID:** 10884158
- **Project number:** 5R01AI174277-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Hyeryun Choe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $824,985
- **Award type:** 5
- **Project period:** 2023-07-07 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884158

## Citation

> US National Institutes of Health, RePORTER application 10884158, In vivo transformation of chimeric antigen receptor B cells for a functional cure of HIV (5R01AI174277-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10884158. Licensed CC0.

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