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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

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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 via a process dependent on phosphoinositide 3-kinase (31, 32, ␤ (ER) (1). In the ER, the MHC/ 2m heterodimer binds 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). 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 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: , 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 able to lyse infected cells, an out- HLA-A and -B but has little impact on the expression of come that pressures 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 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 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/ , 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 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 by tumor susceptibility gene 101-dependent sorting (38, 39). by guest on September 27, 2021 apoptosed cells (53, 54). However, Tat’s effects on dendritic nism for this effect has been demonstrated to be ubiquitination cells are complex. Recently, it was reported that Tat is efficiently of the MHC class I H chain (or a protein associated with it), and taken up by dendritic cells by a process that seems to involve the effect can be blocked by protease inhibition (35, 36). Sep- -mediated endocytosis (55). Once internalized, Tat in- arate motifs within the K3 protein are responsible for the en- duces dendritic cell maturation and thereby, in an interesting twist docytosis of MHC class I molecules and for targeting them for to the Tat story, causes up-regulation of cell surface MHC class I lysosomal degradation in a tumor susceptibility gene 101-de- (as well as MHC class II and costimulatory molecules) (55). pendent sorting process (37, 38). A related virus that is a horse In addition to the effects of Nef and Tat, there are also hints pathogen, equine herpesvirus-1, has likewise been shown to that HIV-1 Vpu may increase the turnover rate of nascent cause endocytosis of cell surface MHC class I molecules (58). MHC class I H chains (14), and that an as-yet-unidentified Another herpesvirus, murine ␥-herpesvirus 68, encodes a K3 HIV-1 protein may block TAP transport of peptides into the protein (mK3) that induces rapid turnover of MHC class I mol- ER (21). Furthermore, HIV-1 Rev has recently been shown to ecules by a mechanism not involving endocytosis (12, 13, 57). influence MHC class I Ag presentation by an indirect mecha- The mK3 protein has been demonstrated to assist the virus in nism (56). The Rev protein assists in the transport of certain escape from T cells during the latent phase of infection (59). other HIV-1 mRNAs, and so it is necessary for the expression of The activity of mK3 initiates the effective degradation of most these other HIV-1 proteins (Gag, Pol, and Env). Asymptomatic HIV-1 carriers tend to have low Rev activity and therefore low murine MHC class I allele products, but there are exceptions, Gag expression, leading to ineffective killing of infected cells by which may be due to differences in trafficking rate or sequence CTL specific for Gag . Notably, such an observation among different MHC class I molecules (12). MHC class I underscores the importance of not restricting studies of MHC/ molecules in assembly complexes awaiting peptides are prefer- virus interaction to the examination of the effect of a single virus entially associated with mK3 (12), and, in fact, the assembly protein in isolation. complex proteins TAP and tapasin are absolutely required for mK3’s effect on MHC class I (60). The absence of TAP or ta- ␥-Herpesviruses: destruction of MHC class I molecules pasin, or MHC class I mutations abrogating interaction with The human pathogen Kaposi’s sarcoma-associated herpesvirus TAP and tapasin, prevent mK3 from binding to MHC class I encodes two gene products, K3 and K5, that are able to reduce and down-regulating its surface expression (60). drastically the number of MHC class I molecules at the cell sur- An ER-resident protein that can cause down-regulation of face by facilitating their endocytosis (33, 34, 57). The mecha- surface MHC class I is also expressed by myxoma virus, which is The Journal of Immunology 4475

Table I. Selected viral proteins that interfere with Ag presentation

Mechanism Virus Protein ␤ Down-regulates MHC class I and 2m transcription HIV-1 Tat

Reduces the MHC class I mRNA level Bovine papillomavirus E5

Inhibits phagocytosis by DCsa and thereby interferes with HIV-1 Secreted Tat cross-presentation, but also induces DC maturation and surface MHC class I up-regulation

Blocks 11S regulator association with the proteasome HIV-1 Tat

Binds TAP in the ER and inhibits peptide translocation HCMV US6

Blocks TAP transport of peptides into the ER HIV-1 Unknown

Prevents TAP association with tapasin Adenovirus E3/19K ␤ Competes for 2m and peptide HCMV UL18

Reduced level lessens the availability of epitopes from other HIV-1 Rev Downloaded from viral proteins

Delays MHC class I egress from the ER HCMV US10

Retains MHC class I molecules in the ER Adenovirus E3/19K

Binds MHC class I in the ER and prevents its egress HCMV US3 http://www.jimmunol.org/

Blocks the transport of MHC class I molecules from the ER MCMV gp40 (m152 product) into the Golgi

Lowers the surface level of MHC class I by facilitating MHC Adenovirus E3/19K class I/APLP-2 interaction

Reduces the quantity of MHC class I protein Bovine papillomavirus E5

Binds MHC class I in the assembly complex and causes rapid Murine ␥-herpesvirus 68 mK3 turnover of MHC class I by guest on September 27, 2021

Increases MHC class I turnover HIV-1 Vpu

Ejects MHC class I molecules into the cytoplasm HCMV US2 and US11

Redirects MHC class I molecules to MCMV gp48 (m06 product)

Retains MHC class I in the Golgi Bovine papillomavirus E5

Increases endocytosis of MHC class I from the cell surface via HIV-1 Nef an allele-specific mechanism

Facilitates MHC class I endocytosis by ubiquitination KSHVa K3 and K5

Complexes with MHC class I in the ER and remains associated MCMV gp34 (m04 product) with it at the cell surface a DC, Dendritic cell; KSHV, Kaposi’s sarcoma-associated herpesvirus. a poxvirus rather than a herpesvirus (61). A unifying character- ␤-Herpesviruses: the masters of evasion istic of this myxoma protein, the Kaposi’s sarcoma-associated ␥ Murine CMV (MCMV) expresses three genes that encode pro- herpesvirus K3 and K5 proteins, and the murine -herpesvirus tein for blocking Ag presentation: m04, m06, and m152.Byuse 68 mK3 proteins is that they all possess a particular type of con- of a set of mutant MCMVs with deletions of the three genes in served structural motif that is correlated with ligase all possible permutations, the effect on the surface expression of activity. Indeed, the myxomavirus M153R protein has been multiple MHC class I allele products was examined (62). These shown to have ubiquitin ligase activity in vitro, and MHC class experiments showed that these MCMV proteins can have syn- I cytoplasmic tail lysines are necessary for down-regulation of ergistic effects, but certain combinations of these proteins are the MHC class I molecules by M153R (39). This characteristic actually antagonistic; thus, this approach revealed a truer pic- sequence motif is also apparent in several other herpesviruses ture of MCMV’s effects on MHC class I in the course of natural and poxviruses (61), raising the possibility that more viruses infection than had been hitherto obtained. may be identified in the future as capable of interfering with Although there is substantial evidence for an MCMV gene, peptide presentation by this same mechanism. m152, affecting the presentation of a particular MCMV 4476 BRIEF REVIEWS: DOWN-REGULATION OF CLASS I MHC EXPRESSION BY VIRAL PROTEINS in vitro, the immunodominance of the same epitope in member of the amyloid precursor protein family (78). APLP2 vivo is not affected by whether m152 is expressed (63). Thus, reduces the number of MHC class I molecules that reach the the effect of MCMV proteins on cells that endogenously ex- cell surface, and E3/19K significantly increases the association press them and their effect on professional APCs that take them of MHC class I with APLP2 (9, 79). Thus, by facilitating MHC up and present their peptides by cross-priming appear to be dis- binding to APLP2, E3/19K can act via APLP2 to inhibit MHC tinct. The impact of MCMV infection on APCs has also been surface expression. In total, a single adenovirus protein, examined in other recent studies. The results from these studies E3/19K, can attack MHC class I by three separate mechanisms, indicate that MCMV does induce down-regulation of MHC serving as a highly resourceful viral weapon against the cellular molecules on dendritic cells and macrophages; however, there immune response. are differences in the effects of immune evasion genes when Cellular transformation by adenovirus type 12 (Ad12) in- APCs and fibroblasts are compared (64–66). For example, ex- duces an oncogenic phenotype (80). One apparent aspect of pression of the m04, m06, and m152 genes are all necessary to this phenotype is the reduction in surface MHC class I mole- block recognition of macrophages by Kb-restricted CTLs, and cules that accompanies Ad12 transformation, allowing escape the m04 gene, in particular, plays a greater role in inhibition of from lysis (81). Relevant to surface down-regulation of T cell recognition in macrophages than in fibroblasts (66). MHC class I, Ad12-transformed cells have decreased expression Human CMV (HCMV) invests heavily in products able to of the MHC H chain, TAP, tapasin, LMP-2, LMP-7, interfere with MHC class I. The HCMV unique short (US) MECL-1, and PA28 (20, 82, 83). Reduced expression of these genes (US2, US3, US6, and US11) all assist HCMV in evading proteins has been attributed to an IFN-related effect (84, 85), Downloaded from MHC class I presentation. HCMV encodes a unique long (UL) and, in the case of MHC class I transcriptional down-regulation, region protein, UL18, which is an MHC class I homolog, ca- dual mechanisms (i.e., repressive COUP-TFII and inactivated ␤ ␬ pable of binding 2m and peptide (67–69). Notably, the sur- NF- B) are used, evidently as mutual back-up measures (86). face expression of UL18 is not affected by US2, US3, US6, or US11, indicating that all of these US proteins accurately discern Papillomavirus: virus and tumor evasion sequence differences between multiple host-encoded MHC Two reports in the last year have indicated that the bovine pap- http://www.jimmunol.org/ molecules and the HCMV-encoded imitator (70). illomavirus E5 protein can down-regulate the surface expres- HCMV US2 (and US11) cause ejection of MHC class I H sion of MHC class I molecules (87, 88). Cells that express E5 chains into the cytoplasm, which results in their proteasomal have reduced levels of MHC class I mRNA and protein and degradation (15, 16). The US2 cytoplasmic domain has been surface MHC class I, whereas surface expression of a control shown to have major involvement in this process (71, 72). Al- protein, the receptor, is not affected (87). E5 can though studies in cultured cell lines did not distinguish US2 retain MHC class I in multiple cell types (87), and the site of block- and US11 in effectiveness, new experiments with primary hu- ade has been shown to be the Golgi (88). Because E5 is a viral on-

man dendritic cells have revealed that US11 is much more ef- coprotein, this finding is of interest from the perspective of tumor, by guest on September 27, 2021 fective than US2 at degrading MHC class I in these cells (73). as well as virus, escape from the specific immune response. US3 possesses a novel, noncontiguous ER retention sequence, and binds to MHC class I to prevent its egress to the cell surface New models: approaching nature (4, 5, 74). US6 inhibits TAP, thereby blocking peptide loading An important new trend in the analysis of MHC class I/virus of HLA-A, -B, and -C molecules, but not HLA-E; this preser- interactions, evidenced by several of the studies described vation of HLA-E expression ensures protection against NK cells above, is the rising frequency of productive investigation of (22–24, 75). Inhibition of TAP has been used successfully as a these interactions in the context of virus infection, using gene- defensive mechanism by other herpesviruses, including a swine deletion virus variants and samples from infected patients. The pathogen, pseudorabies (25), and bovine herpesvirus 1 (26, 76). results obtained with these approaches are providing us an ap- Another HCMV US gene product, US8, has recently been preciation of complementary and antagonistic interactions discovered to bind MHC class I molecules in the ER (77). US8 among the proteins expressed by each virus. Certainly, a future does not quantitatively affect MHC class I surface expression generation of these studies will involve analysis of the impact on (77), although its influence on MHC class I-restricted Ag pre- MHC class I Ag presentation of infections with multiple differ- sentation remains to be more fully explored. In contrast, an- ent chronic viruses, as is often the case in the human situation. other US product, US10, has recently been found to delay the The effects of viruses on MHC class I function are also being migration of folded MHC class I molecules out of the ER, rem- analyzed in recent studies in a wider variety of cell types than iniscent of US3 (6). ever before, including professional APCs. In addition to HIV and MCMV, other viruses, e.g., human herpesvirus 3 (also Adenovirus: fail-safe mechanisms known as varicella-zoster virus), infect dendritic cells and The adenoviral protein E3/19K was first shown to down-regu- down-regulate expression of MHC class I molecules on them late cell surface MHC class I expression by direct retention of (89). Taken together, the findings with APCs suggest that vi- MHC H chains in the ER (7, 8). Later, it was demonstrated that ruses can affect presentation of peptides in these cells, and, in E3/19K also binds to TAP, apart from its direct interaction addition, that there are many functionally important nuances of with the MHC molecule (19). As a result of binding to TAP, viral immune evasion to be discovered when APCs are com- E3/19K blocks the association of TAP with tapasin (19). Re- pared with other cell types. cently, it was found that the E3/19K protein binds preferen- tially to the folded form of the MHC class I molecule, as does The new frontier: viral blocking of NK cell killing the ubiquitous cellular protein amyloid precursor-like protein 2 Although the selective pressure on viruses to down-regulate (APLP2) (9). APLP2 is a type I transmembrane protein and a MHC class I expression for the purpose of avoiding CTL killing The Journal of Immunology 4477 is apparent, the ability of viruses to escape from CTLs without 13. Yu, Y. Y., M. R. Harris, L. Lybarger, L. A. Kimpler, N. B. Myers, H. W. Virgin IV, and T. H. Hansen. 2002. Physical association of the K3 protein of ␥-2 herpesvirus 68 with simultaneously increasing susceptibility to NK cells is intrigu- ␤ major complex class I molecules with impaired peptide and 2- ing. Several recent studies have dealt with this issue, and in the microglobulin assembly. J. Virol. 76:2796. 14. Kerkau, T., I. Bacik, J. R. Bennink, J. W. Yewdell, T. Hunig, A. Schimpl, and process have generated a new immunology subfield: virus inter- U. Schubert. 1997. The human immunodeficiency virus type 1 (HIV-1) Vpu protein ference with NK cell recognition. In one case, the host has interferes with an early step in the of major histocompatibility complex turned the virus’s weapon on itself. In a story replete with evo- (MHC) class I molecules. J. Exp. Med. 185:1295. 15. Wiertz, E. J., T. R. Jones, L. Sun, M. Bogyo, H. J. Geuze, and H. L. Ploegh. 1996. The lutionary twists, a cell surface MCMV protein encoded by human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from m157 binds to an inhibitory NK cell receptor that is expressed the endoplasmic reticulum to the . Cell 84:769. 16. Wiertz, E. J., D. Tortorella, M. Bogyo, J. Yu, W. Mothes, T. R. Jones, T. A. Rapoport, by an MCMV-susceptible mouse strain, and the same m157 and H. L. Ploegh. 1996. -mediated transfer of a membrane protein from the product binds to an activating NK cell receptor in MCMV-re- endoplasmic reticulum to the proteasome for destruction. Nature 384:432. sistant mice (90). 17. Seeger, M., K. Ferrell, R. Frank, and W. Dubiel. 1997. HIV-1 Tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation. J. Biol. Chem. 272:8145. In many cases, the new findings in this area involve viral pro- 18. Huang, X., U. Seifert, U. Salzmann, P. Henklein, R. Preissner, W. Henke, A. J. Sijts, teins that down-regulate MHC class I as well as NK recogni- P.-M. Kloetzel, and W. Dubiel. 2002. The RTP site shared by the HIV-1 Tat protein and the 11 S regulator subunit ␣ is crucial for their effects on proteasome function tion. For example, the m152 gene product of MCMV, which including processing. J. Mol. Biol. 323:771. inhibits the MHC class I expression, also affects NK cell reac- 19. Bennett, E. M., J. R. Bennink, J. W. Yewdell, and F. M. Brodsky. 1999. Adenovirus tivity against MCMV by modulation of NKG2D ligands, spe- E19 has two mechanisms for affecting class I MHC expression. J. Immunol. 162:5049. 20. Rotem-Yehudar, R., M. Groettrup, A. Soza, P. M. Kloetzel, and R. Ehrlich. 1996. cifically retinoic acid early inducible 1 proteins (11, 91–93). LMP-associated proteolytic activities and TAP-dependent peptide transport for class I

The Kaposi’s sarcoma-associated herpesvirus K5 protein, which MHC molecules are suppressed in cell lines transformed by the highly oncogenic ad- Downloaded from enovirus 12. J. Exp. Med. 183:499. down-regulates MHC class I surface expression, also down-reg- 21. Kutsch, O., T. Vey, T. Kerkau, T. Hunig, and A. Schimpl. 2002. HIV type 1 abro- ulates the expression of ICAM-1 and B7-2 molecules and gates TAP- of antigenic peptides presented by MHC class I. AIDS thereby inhibits lysis by NK cells (94). In other cases, viral pro- Res. Hum. Retroviruses 18:1319. 22. Ahn, K., A. Gruhler, B. Galocha, T. R. Jones, E. J. Wiertz, H. L. Ploegh, teins that block NK activity interact with MHC-like molecules. P. A. Peterson, Y. Yang, and K. Fruh. 1997. The ER-luminal domain of the HCMV An HCMV protein (UL16) interferes with the recognition of glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6:613. 23. Hengel, H., J. O. Koopmann, T. Flohr, W. Muranyi, E. Goulmy, G. J. 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