A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity
- Food and Drug Administration, Silver Spring, MD (United States)
- Food and Drug Administration, Silver Spring, MD (United States); Adicet Bio, Inc., Menlo Park, CA (United States)
- Iowa City Veterans Affairs Medical Center, Iowa City, IA (United States); University of Iowa, Iowa City, IA (United States)
- Food and Drug Administration, Silver Spring, MD (United States); AstraZeneca, Gaithersburg, MD (United States)
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.
- Research Organization:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- Grant/Contract Number:
- SC0014664
- OSTI ID:
- 2425572
- Journal Information:
- Gene Therapy, Journal Name: Gene Therapy Journal Issue: 10-11 Vol. 29; ISSN 0969-7128
- Publisher:
- Springer NatureCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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