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Journal of Virology, June 2000, p. 5691-5701, Vol. 74, No. 12
Cold Spring Harbor Laboratory, Cold Spring
Harbor, New York 11724,1 and Institute
for Clinical and Molecular Virology, University of
Erlangen-Nuernberg, 91054 Erlangen, Germany2
Received 24 November 1999/Accepted 10 March 2000
Simian immunodeficiency virus (SIV) and human immunodeficiency
virus type 1 (HIV-1) Nef proteins are related regulatory proteins that
share several functions, including the ability to downregulate class I
major histocompatibility complex (MHC) and CD4 expression on the cell
surface and to alter T-cell-receptor-initiated signal transduction
in T cells. We compared the mechanisms used by SIV mac239 Nef and HIV-1
Nef to downregulate class I MHC and found that the ability of SIV
Nef to downregulate class I MHC requires a unique C-terminal region of
the SIV mac239 Nef molecule which is not found in HIV-1 Nef.
Interestingly, mutation of the PxxP motif in SIV Nef, unlike in HIV-1
Nef, does not affect class I MHC downregulation. We also found that
downregulation of class I MHC by SIV Nef requires a conserved tyrosine
in the cytoplasmic domain of the class I MHC heavy chain and involves
accelerated endocytosis of class I complexes, as previously found with
HIV-1 Nef. Thus, while SIV and HIV-1 Nef proteins use a similar
mechanism to downregulate class I MHC expression, they have evolved
different surfaces for molecular interactions with cell factors that
regulate class I MHC traffic. Mutations in the C-terminal domain
of SIV mac239 Nef selectively disrupt class I MHC
downregulation, having no detectable effect on other functions of
Nef, such as the downregulation of CD4 and CD3 surface expression, the
stimulation of SIV virion infectivity, and the induction of SIV
replication from T cells infected in the absence of stimulation. The
resulting mutants will be useful reagents for studying the importance
of class I MHC downregulation for SIV replication and AIDS pathogenesis
in infected rhesus macaques.
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Simian and Human Immunodeficiency Virus Nef Proteins Use
Different Surfaces To Downregulate Class I Major
Histocompatibility Complex Antigen Expression
*
Corresponding author. Mailing address: Cold Spring
Harbor Laboratory, P.O. Box 100, 1 Bungtown Rd., Cold Spring Harbor, NY 11724. Phone: (516) 367-8407. Fax: (516) 367-8454. E-mail:
skowrons{at}cshl.org.
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