# B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $390,000

## Abstract

PROJECT SUMMARY
Neutralizing antibodies against HIV-1 are very potent in suppressing HIV-1 replication. However, the serum
concentrations of the antibodies must be kept at therapeutic levels for long periods of time to eliminate
HIV-1-infected cells, because persistently infected cells reside in the deep tissue. Therefore, multiple
administrations of the antibodies are required, which could be expensive and labor-intensive. Gene therapy
vectors can be used to produce therapeutic antibodies. However, transgene expression by any gene therapy
vectors, including lentiviral vectors, can induce immune reactions against the transgenes, thereby decreasing
the therapeutic effects of transgene products and eliminating the transduced cells. Therefore, it is important to
express transgenes in the cell types that can develop tolerance to transgene products. B-cells physiologically
express wide varieties of valuable antibody regions generated by recombination and mutations in genes. B-cells
are known to induce tolerance to the valuable regions. This ability of B-cells was previously used to induce
tolerance to self-antigens for therapy of autoimmune diseases and coagulation factor IX for treatment of
hemophilia. Therefore, transduction of B-cells is likely to generate long-term anti-HIV-1 antibodies without
inducing immune reactions to the antibodies. We have developed lentiviral vectors that can specifically
transduce desired target cell types after systemic administration. The vector can selectively transduces splenic
B-cells without conjugation of any B-cell-targeting ligand. By exploiting this B-cell-specific transduction by our
lentiviral vectors, we will attempt to express anti-HIV-1 proteins specifically in B-cells to develop tolerance to the
transgene products. We will further increase specificity of transgene expression with our targeting vector by
combining it with transcriptional B-cell targeting by a B-cell-specific promoter. Using this highly B-cell-specific
transgene expression system, we will express eCD4-Ig, a highly potent anti-HIV-1 reagent consisting of IgG and
soluble CD4, in immunocompetent mice. We will investigate whether eCD4-Ig expression, specifically in B-cells,
can induce long-term expression of eCD4-Ig by inducing developing tolerance. We will next express both
secretory and membrane-anchored forms of eCD4-Ig in B-cells to generate an anti-HIV-1 B-cell receptor (BCR)
on B-cells. We will investigate whether anti-HIV-1 BCR elicits signals upon binding to the HIV-1 envelope protein,
inducing differentiation and growth of the transduced cells. The growth of transduced B-cells will increase the
serum concentrations of eCD4-Ig. Differentiation of transduced cells to memory B-cells and plasma cells will
extend the period of eCD4-Ig expression by prolonging the life span of transduced B-cells. We will then evaluate
the therapeutic effects of B-cell-specific expression of eCD4-Ig in HIV-1 infection of humanized BLT mice. These
experiments a...

## Key facts

- **NIH application ID:** 9873922
- **Project number:** 5R01AI145044-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Koki Morizono
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873922

## Citation

> US National Institutes of Health, RePORTER application 9873922, B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression (5R01AI145044-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873922. Licensed CC0.

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