Virus Evasion of MHC Class I Molecule Presentation Jason L. Petersen, Chantey R. Morris and Joyce C. Solheim This information is current as J Immunol 2003; 171:4473-4478; ; of September 27, 2021. doi: 10.4049/jimmunol.171.9.4473 http://www.jimmunol.org/content/171/9/4473 Downloaded from References This article cites 96 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/171/9/4473.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS Virus Evasion of MHC Class I Molecule Presentation1 Jason L. Petersen,* Chantey R. Morris,* and Joyce C. Solheim2*†‡ he MHC class I H chain and the L chain that assembles docytosis of MHC class I molecules by the ARF6 pathway, and ␤ ␤ 3 with it, 2-microglobulin ( 2m), are cotranslationally the MHC molecules are recycled into the trans-Golgi network T inserted into the lumen of the endoplasmic reticulum via a process dependent on phosphoinositide 3-kinase (31, 32, ␤ (ER) (1). In the ER, the MHC/ 2m heterodimer binds peptide 43). However, the effect of Nef on HLA-A2 expressed in T lym- that is generated by proteasomal protein degradation in the cy- phocytes is predominantly inhibition of transport to the sur- tosol and translocated into the ER by the transporter associated face, rather than facilitation of endocytosis (10). The mecha- with Ag processing (TAP) (Fig. 1) (1, 2). Peptides can be fur- nism of MHC down-modulation may be MHC allele ther trimmed on their N termini by the ER aminopeptidase as- dependent and/or cell dependent (10). For example, the degree sociated with Ag presentation (3). The loading of peptides into of MHC class I cell surface reduction by Nef varies ϳ100-fold Downloaded from MHC class I molecules occurs in an assembly complex that in- depending on the type of cell examined (28, 30, 42, 44), sug- cludes TAP and other chaperones: tapasin, ERp57, and calre- gesting the involvement of cell-specific factors that either assist ticulin (2). Upon peptide binding, MHC class I molecules leave or interfere with Nef’s activity. the ER and traverse to the cell surface via Golgi and vesicular An interesting feature of Nef’s effect on MHC class I is its transport (1). At the surface, the peptides are exposed for rec- sequence specificity. For example, HIV-1 down-regulates http://www.jimmunol.org/ ognition by T lymphocytes able to lyse infected cells, an out- HLA-A and -B but has little impact on the expression of come that pressures viruses to take defensive measures (Table I; HLA-C and -E; this selectivity allows HIV-1-infected cells to Fig. 1) (4–39). Since the first descriptions of adenovirus protein escape lysis by NK cells (45). Physical interaction has been dem- ϳ binding to MHC class I molecules 20 years ago, there have onstrated between Nef and particular amino acid residues been many reports of virus counterattack strategies aimed at the present in the cytoplasmic tail of HLA-A2, but not in HLA-E cellular immune response. This mini-review will focus principally and in site-directed HLA-A2 mutants (27). Importantly, the on reports from the past year dealing with virus efforts against identification of specific binding sites for Nef on MHC mole- MHC class I peptide presentation, although background will be cules may lead to an understanding of differences in AIDS sus- provided to set the stage for each new development. ceptibility or resistance that are linked to particular MHC al- by guest on September 27, 2021 leles. In contrast to its effect on HLA-A2, Nef has very little HIV-1: Nef, Tat, and now Rev effect on murine MHC class I molecules (46), a finding that Considering the relatively small size of the HIV-1 genome, a further adds to our appreciation of the difficulty of deriving a sizable number of HIV-1 gene products have been implicated suitable small-animal model for AIDS. Studies with mouse/hu- in interference with MHC class I Ag presentation. The stron- man MHC chimeras indicate that amino acid residues in the gest evidence is for roles for Nef and Tat in this process. Nef is extracellular domains of the MHC molecule, as well as in the a protein that is unnecessary for HIV-1 replication, but that is cytoplasmic domain, can play a role in Nef-mediated MHC required for the development of the immune deficiencies asso- class I down-modulation (46). ciated with HIV infection (40). Nef increases the pathogenicity The HIV-1 tat gene encodes a protein that transactivates of HIV in several ways, including down-modulation of cell sur- HIV transcription (47). Tat is able to repress MHC class I pro- ␤ face MHC class I molecules (28, 30). Specific regions of Nef moter activity, as well as the activity of the promoter for 2m that are involved in MHC class I down-regulation have been (48–51). Tat is also capable of inhibiting the association of the identified (29, 41). CTL killing of HIV-1-infected primary 11S regulator subunit with the proteasome via a shared binding cells is inefficient if Nef is expressed, and the resistance of the site, interfering with the production of peptides for MHC bind- infected cells is due to MHC class I down-regulation (42). ing (17, 18). Tat is also secreted by HIV-infected cells (52). The To reduce MHC class I surface expression, Nef and phospho- presence of extracellular HIV-1 Tat indirectly affects MHC furin acidic cluster sorting protein-1 cooperate to cause the en- class I presentation by inhibiting dendritic cell phagocytosis of *Eppley Institute for Research in Cancer and Allied Diseases, and Departments of †Pathol- 2 Address correspondence and reprint requests to Dr. Joyce C. Solheim, Eppley Institute ogy and Microbiology and ‡Biochemistry and Molecular Biology, University of Nebraska for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Medical Center, Omaha, NE 68198 986805 Nebraska Medical Center, Omaha, NE 68198-6805. E-mail address: [email protected] Received for publication June 11, 2003. Accepted for publication August 4, 2003. 3 Abbreviations used in this paper: ␤ m, ␤ -microglobulin; ER, endoplasmic reticulum; The costs of publication of this article were defrayed in part by the payment of page charges. 2 2 TAP, transporter associated with Ag processing; MCMV, murine CMV; HCMV, human This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. CMV; US, unique short; UL, unique long; APLP2, amyloid precursor-like protein 2; Section 1734 solely to indicate this fact. Ad12, adenovirus type 12. 1 This work was supported by National Institutes of Health Grant GM57428 (to J.C.S.), by National Institutes of Health Training Grant T32 CA09476, and by National Institutes of Health Individual National Research Service Award Fellowships (to J.L.P. and C.R.M.). Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 4474 BRIEF REVIEWS: DOWN-REGULATION OF CLASS I MHC EXPRESSION BY VIRAL PROTEINS Downloaded from FIGURE 1. Diagram of MHC class I assembly and transport (1–3). MHC class I H chain and ␤ m assemble with peptide in a multimeric complex with 2 http://www.jimmunol.org/ calreticulin, ERp57, tapasin, and the TAP heterodimer in the ER (2). Certain viral proteins retard MHC class I egress or induce its turnover, in some cases by ejection of the molecules from the ER into the cytoplasm (4–16). Peptides are provided by proteasomal cleavage of ubiquitinated cytosolic proteins and TAP transport into the ER (2), and both TAP and the proteasome are known targets for viral interference (17–26). Within the ER, the peptides are N-terminally trimmed by ER aminopeptidase associated with Ag presentation (ERAAP) (3). Once peptide is bound, the complete MHC class I molecule is released from ER chaperones and proceeds through the Golgi (1). Via vesicular transport, the MHC class I molecule reaches the cell surface where it can present peptide to CTL (1). After the arrival of MHC class I molecules at the cell surface, certain virus proteins can cause their endocytosis. For example, HIV-1 Nef binds MHC class I on its cytoplasmic tail and escorts it from the cell membrane into the endosomal compartment (27, 28). These MHC molecules are subsequently degraded, or they are transported into the trans-Golgi with the assistance of protein transport proteins like phosphofurin acidic cluster sorting protein-1, adaptor protein complexes, and phosphoinositide 3-kinase (27, 29–32). Some virus proteins facilitate the endocytosis of MHC class I molecules by ubiquitination (33–37), and one of these proteins, the Kaposi’s sarcoma-associated herpesvirus K3 protein, has been specifically shown to direct these endocytosed MHC class I molecules to the lysosome by tumor susceptibility gene 101-dependent sorting (38, 39).