1. Altered HIV-1 mRNA Splicing Due to Drug-Resistance-Associated Mutations in Exon 2/2b
- Author
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Lisa Müller, Wiebke Moskorz, Anna-Lena Brillen, Frank Hillebrand, Philipp Niklas Ostermann, Niklas Kiel, Lara Walotka, Johannes Ptok, Jörg Timm, Nadine Lübke, and Heiner Schaal
- Subjects
QH301-705.5 ,RNA Splicing ,HIV Integrase ,Regulatory Sequences, Nucleic Acid ,Virus Replication ,Article ,SREs ,Catalysis ,Cell Line ,Inorganic Chemistry ,splicing ,Drug Resistance, Viral ,Humans ,HIV Integrase Inhibitors ,RNA, Messenger ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,Organic Chemistry ,Exons ,General Medicine ,HIV-1 ,Computer Science Applications ,Chemistry ,HEK293 Cells ,Mutation ,RNA Splice Sites ,HeLa Cells - Abstract
The underlying molecular mechanism and their general effect on the replication capacity of HIV 1 drug-resistance-associated mutations is often poorly understood. To elucidate the effect of two such mutations located in a region with a high density of spicing regulatory elements on the HIV-1-splicing outcome, bioinformatic predictions were combined with transfection and infection experiments. Results show that the previously described R263K drug-resistance-associated integrase mutation has additionally a severe effect on the ESE2b splicing regulatory element (SRE) in exon 2b, which causes loss of SD2b recognition. This was confirmed by an R263R silent mutation with a similar predicted effect on the exon 2b SRE. In contrast, a V260I mutation and its silent counterpart with a lower effect on ESS2b did not exhibit any differences in the splicing pattern. Since HIV-1 highly relies on a balanced splicing reaction, changes in the splicing outcome can contribute to changes in viral replication and might add to the effect of escape mutations toward antiviral drugs. Thus, a classification of mutations purely addressing proteins is insufficient.
- Published
- 2021