Minimal impact of ZAP on lentiviral vector production and transduction efficiency.

Autor:	Sertkaya H; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Hidalgo L; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Ficarelli M; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Kmiec D; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Signell AW; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Ali S; Cell & Gene Therapy Platform, Medicinal Science and Technology, GSK, Stevenage SG1 2NY, UK., Parker H; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Wilson H; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Neil SJD; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Malim MH; Department of Infectious Diseases, King's College London, London SE1 9RT, UK., Vink CA; Cell & Gene Therapy Platform, Medicinal Science and Technology, GSK, Stevenage SG1 2NY, UK., Swanson CM; Department of Infectious Diseases, King's College London, London SE1 9RT, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2021 Aug 28; Vol. 23, pp. 147-157. Date of Electronic Publication: 2021 Aug 28 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2021.08.008
Abstrakt:	The antiviral protein ZAP binds CpG dinucleotides in viral RNA to inhibit replication. This has likely led to the CpG suppression observed in many RNA viruses, including retroviruses. Sequences added to retroviral vector genomes, such as internal promoters, transgenes, or regulatory elements, substantially increase CpG abundance. Because these CpGs could allow retroviral vector RNA to be targeted by ZAP, we analyzed whether it restricts vector production, transduction efficiency, and transgene expression. Surprisingly, even though CpG-high HIV-1 was efficiently inhibited by ZAP in HEK293T cells, depleting ZAP did not substantially increase lentiviral vector titer using several packaging and genome plasmids. ZAP overexpression also did not inhibit lentiviral vector titer. In addition, decreasing CpG abundance in a lentiviral vector genome did not increase its titer, and a gammaretroviral vector derived from murine leukemia virus was not substantially restricted by ZAP. Overall, we show that the increased CpG abundance in retroviral vectors relative to the wild-type retroviruses they are derived from does not intrinsically sensitize them to ZAP. Further understanding of how ZAP specifically targets transcripts to inhibit their expression may allow the development of CpG sequence contexts that efficiently recruit or evade this antiviral system. Competing Interests: The authors declare no competing interests. (© 2021 The Authors.)
Databáze:	MEDLINE
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