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Journal of Virology, October 2003, p. 10548-10556, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10548-10556.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Down-Modulation of Mature Major Histocompatibility Complex Class II and Up-Regulation of Invariant Chain Cell Surface Expression Are Well-Conserved Functions of Human and Simian Immunodeficiency Virus nef Alleles

Michael Schindler,1 Stephanie Würfl,1 Philippe Benaroch,2 Thomas C. Greenough,3 Rod Daniels,4 Philippa Easterbrook,5 Matthias Brenner,1 Jan Münch,1 and Frank Kirchhoff1*

Department of Virology, Universitätsklinikum, 89081 Ulm, Germany,1 Institut Curie, Inserm U520, 75005 Paris, France,2 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605,3 Virology Division, National Institute for Medical Research, London NW7 1AA,4 Department of HIV/GUM, GKT School of Medicine, Weston Education Centre, London SE5 9RJV, United Kingdom5

Received 6 March 2003/ Accepted 7 July 2003

Recently, it has been demonstrated that the human immunodeficiency virus type 1 (HIV-1) Nef from laboratory strains down-modulates cell surface expression of mature major histocompatibility complex class II (MHC-II) molecules, while up-regulating surface expression of the invariant chain (Ii) associated with immature MHC-II (P. Stumptner-Cuvelette, S. Morchoisne, M. Dugast, S. Le Gall, G. Raposo, O. Schwartz, and P. Benaroch, Proc. Natl. Acad. Sci. USA 98:12144-12149, 2001). These Nef functions could contribute to impaired CD4+-T-helper-cell responses found in HIV-1-infected patients with progressive disease. However, it is currently unknown whether nef alleles derived from HIV-1-infected individuals or from other primate lentiviruses also modulate MHC-II and Ii. In the present study, we demonstrate that both activities are conserved among primary HIV-1 nef alleles, as well as among HIV-2 and simian immunodeficiency virus (SIV) nef alleles. Down-modulation of mature MHC-II required high levels of Nef expression. In contrast, surface expression of Ii was already strongly increased at low to medium levels of Nef expression. Notably, nef genes derived from two of four HIV-1-infected long-term nonprogressors did not up-regulate Ii, whereas nef alleles derived from 10 individuals with progressive disease were active in this assay. Unlike other in vitro Nef functions, the average activity of Nef in modulating MHC-II and Ii surface expression did not change significantly during the course of infection. Mutational analysis confirmed that MHC-II down- and Ii up-regulation are functionally separable from each other and from other Nef functions and identified acidic residues, located at the base of the flexible C-proximal loop of Nef, that are critical for increased Ii expression. Overall, our results suggest that the ability of Nef to interfere with MHC-II antigen presentation might play a role in AIDS pathogenesis.

* Corresponding author. Mailing address: Department of Virology, Universitätsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49-731-50023344. Fax: 49-731-50023337. E-mail: frank.kirchhoff{at}medizin.uni-ulm.de.

Journal of Virology, October 2003, p. 10548-10556, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10548-10556.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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