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J. Biol. Chem., Vol. 281, Issue 27, 18644-18651, July 7, 2006

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A Novel Splice Donor Site in the gag-pol Gene Is Required for HIV-1 RNA Stability^*

Martin Lützelberger, Line S. Reinert, Atze T. Das, Ben Berkhout, and Jørgen Kjems¹

From the Department of Molecular Biology, University of Aarhus, C. F. Møllers Allé 130, 8000 Århus C, Denmark and the Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam P. O. Box 22660, 1100 DD Amsterdam, The Netherlands

Productive infection and successful replication of human immunodeficiency virus 1 (HIV-1) requires the balanced expression of all viral genes. This is achieved by a combination of alternative splicing events and regulated nuclear export of viral RNA. Because viral splicing is incomplete and intron-containing RNAs must be exported from the nucleus where they are normally retained, it must be ensured that the unspliced HIV-1 RNA is actively exported from the nucleus and protected from degradation by processes such as nonsense-mediated decay. Here we report the identification of a novel 178-nt-long exon located in the gag-pol gene of HIV-1 and its inclusion in at least two different mRNA species. Although efficiently spliced in vitro, this exon appears to be tightly repressed and infrequently used in vivo. The splicing is activated or repressed in vitro by the splicing factors ASF/SF2 and heterogeneous nuclear ribonucleoprotein A1, respectively, suggesting that splicing is controlled by these factors. Interestingly, mutations in the 5'-splice site resulted in a dramatic reduction in the steady-state level of HIV-1 RNA, and this effect was partially reversed by expression of U1 small nuclear RNA harboring the compensatory mutation. This implies that U1 small nuclear RNA binding to optimal but non-functional splice sites might have a role in protecting unspliced HIV-1 mRNA from degradation.

Received for publication, December 23, 2005 , and in revised form, March 23, 2006.

^* This work was supported by the Danish National Research Foundation, Danish Natural Research Council, The AIDS Foundation, and The Carlsberg Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 45-8942-2686; Fax: 45-8619-6500; E-mail: jk{at}mb.au.dk.

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