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Journal of Virology, September 2001, p. 8137-8146, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8137-8146.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Simian Immunodeficiency Virus in Which nef and U3 Sequences Do Not Overlap Replicates Efficiently In Vitro and In Vivo in Rhesus Macaques

Jan Münch,1,dagger Nadia Adam,1 Nathaly Finze,1 Nicole Stolte,2 Christiane Stahl-Hennig,2 Dietmar Fuchs,3 Peter Ten Haaft,4 Jonathan L. Heeney,4 and Frank Kirchhoff1,*

Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, 91054 Erlangen,1 and German Primate Center, 37077 Göttingen,2 Germany; Institute of Medical Chemistry and Biochemistry, University of Innsbruck, and Ludwig Bolzmann Institute of AIDS Research, A-6020 Innsbruck, Austria3; and Department of Virology, Biomedical Primate Research Center, 2288 GJ Rijswijk, The Netherlands4

Received 26 March 2001/Accepted 21 May 2001

The nef genes of human immunodeficiency virus and simian immunodeficiency virus (SIV) overlap about 80% of the U3 region of the 3' long terminal repeat (LTR) and contain several essential cis-acting elements (here referred to as the TPI region): a T-rich region, the polypurine tract, and attachment (att) sequences required for integration. We inactivated the TPI region in the nef reading frame of the pathogenic SIVmac239 clone (239wt) by 13 silent point mutations. To restore viral infectivity, intact cis-regulatory elements were inserted just downstream of the mutated nef gene. The resulting SIV genome contains U3 regions that are 384 bp shorter than the 517-bp 239wt U3 region. Overall, elimination of the duplicated Nef coding sequences truncates the proviral genome by 350 bp. Nonetheless, it contains all known coding sequences and cis-acting elements. The TPI mutant virus expressed functional Nef and replicated like 239wt in all cell culture assays and in vivo in rhesus macaques. Notably, these SIVmac constructs allow us to study Nef function in the context of replication-competent viruses without the restrictions of overlapping LTR sequences and important cis-acting elements. The genomes of all known primate lentiviruses contain a large overlap between nef and the U3 region. We demonstrate that this conserved genomic organization is not obligatory for efficient viral replication and pathogenicity.

* Corresponding author. Mailing address: Abteilung Virologie, Institut für Mikrobiologie und Immunologie, Unversitätsklinikum Ulm, Ulm, Germany. Phone: 49-731-5002 3344. Fax: 49-731-5002 3389. E-mail: frank.kirchhoff{at}medizin.uni-ulm.de.

dagger Present address: Abteilung Virologie, Institut für Mikrobiologie und Immunologie, Unversitätsklinikum Ulm, Ulm, Germany.

Journal of Virology, September 2001, p. 8137-8146, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8137-8146.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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