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Journal of Virology, May 2000, p. 4155-4164, Vol. 74, No. 9
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Simian Immunodeficiency Virus Containing Mutations in N-Terminal Tyrosine Residues and in the PxxP Motif in Nef Replicates Efficiently in Rhesus Macaques

Silke Carl,1 A. John Iafrate,2 Sabine M. Lang,1 Nicole Stolte,3 Christiane Stahl-Hennig,3 Kerstin Mätz-Rensing,3 Dietmar Fuchs,4 Jacek Skowronski,2 and Frank Kirchhoff1,*

Institute for Clinical and Molecular Virology, University of Erlangen-Nuernberg, 91054 Erlangen,1 and German Primate Center, 37077 Göttingen,3 Germany; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 117242; and Institute of Medical Chemistry and Biochemistry, University of Innsbruck, and Ludwig Bolzmann Institute of AIDS Research, A-6020 Innsbruck, Austria4

Received 7 December 1999/Accepted 8 February 2000

SIVmac Nef contains two N-terminal tyrosines that were proposed to be part of an SH2-ligand domain and/or a tyrosine-based endocytosis signal and a putative SH3-ligand domain (P104xxP107). In the present study, we investigated the effects of combined mutations in these tyrosine and proline residues on simian immunodeficiency virus (SIV) Nef interactions with the cellular signal transduction and endocytic machinery. We found that mutation of Y28F, Y39F, P104A, and P107A (FFAA-Nef) had little effect on Nef functions such as the association with the cellular tyrosine kinase Src, downregulation of cell surface expression of CD4 and class I major histocompatibility complex, and enhancement of virion infectivity. However, mutations in the PxxP sequence reduced the ability of Nef to stimulate viral replication in primary lymphocytes. Three macaques infected with the SIVmac239 FFAA-Nef variant showed high viral loads during the acute phase of infection. Reversions in the mutated prolines were observed between 12 and 20 weeks postinfection. Importantly, reversion of A107right-arrowP, which restored the ability of Nef to coprecipitate a 62-kDa phosphoprotein in in vitro kinase assays, did not precede the development of a high viral load. The Y28/Y39right-arrowF28/F39 substitutions did not revert. In conclusion, mutations in both the tyrosine residues and the putative SH3 ligand domain apparently do not disrupt major aspects of SIV Nef function 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, May 2000, p. 4155-4164, Vol. 74, No. 9
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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