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Journal of Virology, December 2004, p. 13335-13344, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13335-13344.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus

Tomek Swigut ,1,{dagger},{ddagger} Louis Alexander,2,{dagger} Jennifer Morgan,3 Jeff Lifson,4 Keith G. Mansfield,3 Sabine Lang,3 R. Paul Johnson,3 Jacek Skowronski,1 and Ronald Desrosiers3*

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York,1 Department of Epidemiology and Public Health, Yale Medical School, New Haven, Connecticut,2 New England Primate Research Center, Southborough, Massachusetts,3 Laboratory of Retroviral Pathogenesis, AIDS Vaccine Program, SAIC Frederick Cancer Research and Development Center, Frederick, Maryland4

Received 26 May 2004/ Accepted 2 July 2004

Functional activities that have been ascribed to the nef gene product of simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) include CD4 downregulation, major histocompatibility complex (MHC) class I downregulation, downregulation of other plasma membrane proteins, and lymphocyte activation. Monkeys were infected experimentally with SIV containing difficult-to-revert mutations in nef that selectively eliminated MHC downregulation but not these other activities. Monkeys infected with these mutant forms of SIV exhibited higher levels of CD8+ T-cell responses 4 to 16 weeks postinfection than seen in monkeys infected with the parental wild-type virus. Furthermore, unusual compensatory mutations appeared by 16 to 32 weeks postinfection which restored some or all of the MHC-downregulating activity. These results indicate that nef does serve to limit the virus-specific CD8 cellular response of the host and that the ability to downregulate MHC class I contributes importantly to the totality of nef function.

* Corresponding author. Mailing address: New England Primate Research Center, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102. Phone: (508) 624-8042. Fax: (508) 624-8190. E-mail: Ronald_desrosiers{at}hms.harvard.edu.

{dagger} Co-first authors contributed to similar extents.

{ddagger} Present address: Laboratory of Vertebrate Embryology, The Rockefeller University, New York, NY 10021.

Journal of Virology, December 2004, p. 13335-13344, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13335-13344.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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