Journal article
A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity
Gene therapy, Vol.29(10-11), pp.616-623
11/2022
DOI: 10.1038/s41434-021-00302-5
PMCID: PMC9091046
PMID: 34759330
Abstract
Viral vector-mediated gene therapies have the potential to treat many human diseases; however, host immune responses against the vector and/or the transgene pose a safety risk to the patients and can negatively impact product efficacy. Thus, novel strategies to reduce vector immunogenicity are critical for the advancement of these therapies. T cell activation (TCA) is required for the development of immune responses during gene therapy. We hypothesized that modulation of TCA by incorporating a novel viral immunomodulatory factor into a viral vector may reduce unwanted TCA and immune responses during gene therapy. To test this hypothesis, we identified an immunomodulatory domain of the hepatitis C virus (HCV) NS protein 5A (NS5A) protein and studied the effect of viral vectors expressing NS5A peptide on TCA. Lentiviral vector-mediated expression of a short 20-mer peptide derived from the NS5A protein in human T cells was sufficient to inhibit TCA. Synthetic 20-mer NS5A peptide also inhibited TCA in primary human T cells. Mechanistically, the NS5A protein interacted with Lck and inhibited proximal TCR signaling. Importantly, NS5A peptide expression did not cause global T cell signaling dysfunction as distal T cell signaling was not inhibited. Finally, recombinant adeno-associated virus (AAV) vector expressing the 20-mer NS5A peptide reduced both the recall antigen and the TCR-mediated activation of human T cells and did not cause global T cell signaling dysfunction. Together, these data suggest that expression of a 20-mer NS5A peptide by an AAV vector may reduce unwanted TCA and may contribute to lower vector immunogenicity during gene therapy.
Details
- Title: Subtitle
- A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity
- Creators
- Winston Colon-Moran - Center for Biologics Evaluation and ResearchAlan Baer - Center for Biologics Evaluation and ResearchGauri Lamture - Center for Biologics Evaluation and ResearchJack T. Stapleton - University of IowaJoseph W. Fischer - Center for Biologics Evaluation and ResearchNirjal Bhattarai - Center for Biologics Evaluation and Research
- Resource Type
- Journal article
- Publication Details
- Gene therapy, Vol.29(10-11), pp.616-623
- DOI
- 10.1038/s41434-021-00302-5
- PMID
- 34759330
- PMCID
- PMC9091046
- NLM abbreviation
- Gene Ther
- ISSN
- 0969-7128
- eISSN
- 1476-5462
- Publisher
- Springer Nature
- Number of pages
- 8
- Grant note
- US Food and Drug Administration Intramural Research Program of the Center for Biologics Evaluation and Research (CBER)
- Language
- English
- Electronic publication date
- 11/11/2021
- Date published
- 11/2022
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Internal Medicine
- Record Identifier
- 9984297315402771
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