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Indole-related compounds from the National Cancer Institute (USA) repository do not inhibit HIV-1 replication in primary blood mononuclear cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Indole derived substances have been shown previously to inhibit HIV-1 replication, presumably by interfering with cellular splicing factors of the SR protein family. Here we have tested the effect of indole-related substances obtained from the NCI repository on HIV-1 gene expression in transient transfections and in primary cell cultures infected by X4 and R5 tropic HIV-1 strains. Although these substances displayed a significant inhibitory effect on HIV-1 gene expression in transiently transfected cells, they did not inhibit replication of HIV-1 in primary peripheral blood mononuclear cells. These results demonstrate important differences between transfection assays performed in cell lines and infection assays performed in primary cells and indicate that only a subset of indole-related compounds can inhibit HIV-1 replication.

National Category
Basic Medicine
Research subject
Medical Virology
Identifiers
URN: urn:nbn:se:uu:diva-170300OAI: oai:DiVA.org:uu-170300DiVA: diva2:508945
Available from: 2012-03-11 Created: 2012-03-11 Last updated: 2012-04-19
In thesis
1. Regulation of HIV-1 mRNA Processing by Cellular Splicing Factors
Open this publication in new window or tab >>Regulation of HIV-1 mRNA Processing by Cellular Splicing Factors
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

According to UNAIDS there were 34 million people living with human immunodeficiency virus (HIV) infection at the end of 2010. HIV is the causative agent of acquired immunodeficiency syndrome (AIDS) and the number of people dying of AIDS-related causes at the end of 2010 was 1.8 million. Due to the high mutability of the virus, there is a constant need for new approaches to attack the virus.

Splicing of HIV-1 pre-mRNA is a highly regulated process. In order to produce all mRNAs needed to be infectious HIV-1 utilizes alternative splicing ­- from one single transcript more than 35 differently spliced mRNAs can be produced. A new approach to fight HIV-1 could be to interfere with the essential splicing. In this thesis, I describe the regulation of HIV-1 pre-mRNA splicing.

SR proteins are involved in the regulation of splicing, both in an early and a late stage. We find that the intracellular concentration of SR proteins is of great importance for HIV-1 to be able to produce the correct amounts of mRNAs. Variations in concentrations of SR proteins lead to big changes in the HIV-1 pre-mRNA splicing pattern.

The functions of HIV-1 protein Vpr are diverse and it is essential in vivo. HIV-1 vpr mRNA 13a7 is partially spliced, containing an intron, and the regulation of it is not fully understood. We find that SRp55 and SRp75 induce the production of HIV-1 vpr mRNA 13a7 by inhibiting splice donor 3. We also conclude that this inhibition at least for SRp55 is due to an interaction with the viral RNA element GAR. In the presence of SRp55 we also see an increase in cytoplasmic amounts of intron containing vpr mRNA due to increased nuclear export. Our results show that SRp55 can have several functions in the regulation of HIV-1 splicing: by inhibiting splice donors and by facilitating the export of incompletely spliced mRNAs to the cytoplasm.

In conclusion, this thesis describes SRp55 as a regulator of HIV-1 vpr mRNA, both in splicing as well as in nuclear export. These discoveries provide an insight into the regulation of HIV-1 mRNA processing.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 749
Keyword
HIV-1, SR protein, SRp55, SFRS6, splicing, indole derivative
National Category
Microbiology in the medical area
Research subject
Medical Virology
Identifiers
urn:nbn:se:uu:diva-169256 (URN)978-91-554-8300-5 (ISBN)
Public defence
2012-04-26, C10:301, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-04-04 Created: 2012-02-25 Last updated: 2012-04-19Bibliographically approved

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