[Frontiers in Bioscience 14, 2714-2729, January 1, 2009]

Role of RNA structure and protein factors in the control of HIV-1 splicing

Jean-Michel Saliou1, Cyril F. Bourgeois2,3,4,5, Lilia Ayadi-Ben Mena1, Delphine Ropers1, Sandrine Jacquenet1, Virginie Marchand1, James Stevenin2,3,4,5, Christiane Branlant1

1 MAEM, UMR 7567 CNRS-UHP, Nancy Universite, Faculte des sciences et techniques, BP239, Vandoeuvre Les Nancy CEDEX, France, 2 IGBMC, Department of Functional Genomics, Illkirch, F-67400 France, 3 INSERM, U596, Illkirch, F-67400 France, 4 CNRS, UMR7104, Illkirch, F-67400 France, 5 Universite Louis Pasteur, Strasbourg, F-67000 France

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Overview of HIV-1 alternative splicing in the context of viral infection
4. A small regulatory element that folds into a stem-loop structure controls site A2 utilization
5. A complex extended exon region regulates site A3 utilization
6. Site A7 is regulated by downstream and upstream elements
7. Regulatory elements located in other HIV-1 RNA regions
8. HnRNP A1 a general host down-regulator of HIV-1 RNA splicing
9. Viral proteins may limit HIV-1 RNA splicing
10. Conclusions: lessons from HIV-1 splicing for the design of future therapies
11. Acknowledgments
12. References

1. ABSTRACT

Alternative splicing plays a key role in the production of numerous proteins by complex lentiviruses such as HIV-1. The study of HIV-1 RNA splicing has provided useful information not only about the physiology of the virus, but also about the general mechanisms that regulate mammalian pre-mRNA alternative splicing. Like all retroviruses, a fraction of HIV-1 transcripts remains intact to serve as genomic RNA and to code for Gag and Gag-Pol protein precursors. In addition, splicing is important for controlling the production of some viral proteins, which could otherwise have a negative effect on the infected cell. Here, we summarize how the utilization of HIV-1 splicing sites is limited by the binding of nuclear factors to cis-acting silencer elements, taking into account the role of RNA secondary structure in these mechanisms. We also describe how the poorly efficient HIV-1 acceptor sites are nevertheless activated by serine/arginine-rich proteins. Finally, we discuss how nuclear factors that interact with both the transcription and splicing machineries also participate in the control of HIV-1 RNA splicing.