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Journal of Virology, October 1999, p. 8371-8383, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Human Immunodeficiency Virus Type 1 nef Gene Can to a Large Extent Replace Simian Immunodeficiency Virus nef In Vivo

Frank Kirchhoff,1,* Jan Münch,1 Silke Carl,1 Nicole Stolte,2 Kerstin Mätz-Rensing,2 Dietmar Fuchs,2 Peter Ten Haaft,3 Jonathan L. Heeney,3 Tomek Swigut,4 Jacek Skowronski,4 and Christiane Stahl-Hennig2

Institute for Clinical and Molecular Virology, University of Erlangen-Nuernberg, 91054 Erlangen,1 and German Primate Center, 37077 Göttingen,2 Germany; Biomedical Primate Research Center, Department of Virology, 2288 GJ Rijswijk, The Netherlands3; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 117244

Received 29 December 1998/Accepted 12 July 1999

The nef gene of the pathogenic simian immunodeficiency virus (SIV) 239 clone was replaced with primary human immunodeficiency virus type 1 (HIV-1) nef alleles to investigate whether HIV-1 Nef can substitute for SIV Nef in vivo. Initially, two rhesus macaques were infected with the chimeric viruses (Nef-SHIVs). Most of the nef alleles obtained from both animals predicted intact open reading frames. Furthermore, forms containing upstream nucleotide substitutions that enhanced expression of the inserted gene became predominant. One animal maintained high viral loads and slowly progressed to immunodeficiency. nef long terminal repeat sequences amplified from this animal were used to generate a second generation of Nef-SHIVs. Two macaques, which were subsequently infected with a mixture of cloned chimeric viruses, showed high viral loads and progressed to fatal immunodeficiency. Five macaques received a single molecular clone, named SHIV-40K6. The SHIV-40K6 nef allele was active in CD4 and class I major histocompatibility complex downregulation and enhanced viral infectivity and replication. Notably, all of the macaques inoculated with SHIV-40K6 showed high levels of viral replication early in infection. During later stages, however, the course of infection was variable. Three animals maintained high viral loads and developed immunodeficiency. Of the remaining two macaques, which showed decreasing viral loads after the acute phase of infection, only one efficiently controlled viral replication and remained asymptomatic during 1.5 years of follow-up. The other animal showed an increasing viral load and developed signs of progressive infection during later stages. Our data demonstrate that HIV-1 nef can, to a large extent, functionally replace SIVmac nef in vivo.

* Corresponding author. Mailing address: Institute for Clinical and Molecular Virology, University of Erlangen-Nuernberg, Schlossgarten 4, 91054 Erlangen, Germany. Phone: 49-9131-852 6483. Fax: 49-9131-852 2101. E-mail: fkkirchh{at}viro.med.uni-erlangen.de.

Journal of Virology, October 1999, p. 8371-8383, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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