Universität zu Köln

Hillebrand, Frank, Ostermann, Philipp Niklas ORCID: 0000-0002-4419-6119, Mueller, Lisa, Degrandi, Daniel, Erkelenz, Steffen, Widera, Marek ORCID: 0000-0001-5417-9307, Pfeffer, Klaus and Schaal, Heiner ORCID: 0000-0002-1636-4365 (2019). Gymnotic Delivery of LNA Mixmers Targeting Viral SREs Induces HIV-1 mRNA Degradation. Int. J. Mol. Sci., 20 (5). BASEL: MDPI. ISSN 1422-0067

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Abstract

Transcription of the HIV-1 provirus generates a viral pre-mRNA, which is alternatively spliced into more than 50 HIV-1 mRNAs encoding all viral proteins. Regulation of viral alternative splice site usage includes the presence of splicing regulatory elements (SREs) which can dramatically impact RNA expression and HIV-1 replication when mutated. Recently, we were able to show that two viral SREs, G(I3)-2 and ESEtat, are important players in the generation of viral vif, vpr and tat mRNAs. Furthermore, we demonstrated that masking these SREs by transfected locked nucleic acid (LNA) mixmers affect the viral splicing pattern and viral particle production. With regard to the development of future therapeutic LNA mixmer-based antiretroviral approaches, we delivered the G(I3)-2 and the ESEtat LNA mixmers nakedly, without the use of transfection reagents (gymnosis) into HIV-1 infected cells. Surprisingly, we observed that gymnotically-delivered LNA mixmers accumulated in the cytoplasm, and seemed to co-localize with GW bodies and induced degradation of mRNAs containing their LNA target sequence. The G(I3)-2 and the ESEtat LNA-mediated RNA degradation resulted in abrogation of viral replication in HIV-1 infected Jurkat and PM1 cells as well as in PBMCs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hillebrand, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Ostermann, Philipp Niklas UNSPECIFIED orcid.org/0000-0002-4419-6119 UNSPECIFIED Mueller, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Degrandi, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Erkelenz, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Widera, Marek UNSPECIFIED orcid.org/0000-0001-5417-9307 UNSPECIFIED Pfeffer, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaal, Heiner UNSPECIFIED orcid.org/0000-0002-1636-4365 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-155078
DOI:	10.3390/ijms20051088
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	20
Number:	5
Date:	2019
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANTISENSE OLIGONUCLEOTIDES; IN-VITRO; PROTEINS; REPLICATION; ACTIVATION; INHIBITION; EXPRESSION; BODIES; TAT; MECHANISMS Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15507