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Journal of Virology, November 2000, p. 9836-9844, Vol. 74, No. 21
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Disrupting Surfaces of Nef Required for Downregulation of CD4 and for Enhancement of Virion Infectivity Attenuates Simian Immunodeficiency Virus Replication In Vivo

A. John Iafrate,1 Silke Carl,2 Scott Bronson,1 Christiane Stahl-Hennig,3 Tomek Swigut,1 Jacek Skowronski,1,* and Frank Kirchhoff2

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724,1 and Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, 91054 Erlangen,2 and German Primate Center, 37077 Göttingen,3 Germany

Received 31 May 2000/Accepted 4 August 2000

The multifunctional simian and human immunodeficiency virus (SIV and HIV) Nef proteins are important for virulence. We studied the importance of selected Nef functions using an SIV Nef with mutations in two regions that are required for CD4 downregulation. This Nef mutant is defective for downregulating CD4 and, in addition, for enhancing SIV infectivity and induction of SIV replication from infected quiescent peripheral blood mononuclear cells, but not for other known functions, including downregulation of class I major histocompatibility complex (MHC) cell surface expression. Replication of SIV containing this Nef variant in rhesus monkeys was attenuated early during infection. Subsequent increases in viral load coincided with selection of reversions and second-site compensatory changes in Nef. Our results indicate that the surfaces of Nef that mediate CD4 downregulation and the enhancement of virion infectivity are critical for SIV replication in vivo. Furthermore, these findings indicate that class I MHC downregulation by Nef is not sufficient for SIV virulence early in infection.

* Corresponding author. Mailing address: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724. Phone: (516) 367-8407. Fax: (516) 367-8454. E-mail: skowrons{at}cshl.org.

Journal of Virology, November 2000, p. 9836-9844, Vol. 74, No. 21
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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