The MHC class I H chain and the L chain that assembles with it, β2-microglobulin (β2m),3 are cotranslationally inserted into the lumen of the endoplasmic reticulum (ER) (1). In the ER, the MHC/β2m heterodimer binds peptide that is generated by proteasomal protein degradation in the cytosol and translocated into the ER by the transporter associated with Ag processing (TAP) (Fig. 1) (1, 2). Peptides can be further trimmed on their N termini by the ER aminopeptidase associated with Ag presentation (3). The loading of peptides into MHC class I molecules occurs in an assembly complex that includes TAP and other chaperones: tapasin, ERp57, and calreticulin (2). Upon peptide binding, MHC class I molecules leave the ER and traverse to the cell surface via Golgi and vesicular transport (1). At the surface, the peptides are exposed for recognition by T lymphocytes able to lyse infected cells, an outcome that pressures viruses to take defensive measures (Table I; Fig. 1) (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39). Since the first descriptions of adenovirus protein binding to MHC class I molecules ∼20 years ago, there have been many reports of virus counterattack strategies aimed at the cellular immune response. This mini-review will focus principally on reports from the past year dealing with virus efforts against MHC class I peptide presentation, although background will be provided to set the stage for each new development.

FIGURE 1.

Diagram of MHC class I assembly and transport (123 ). MHC class I H chain and β2m assemble with peptide in a multimeric complex with 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 (45678910111213141516 ). 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 (17181920212223242526 ). 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 (2728 ). 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 (2729303132 ). Some virus proteins facilitate the endocytosis of MHC class I molecules by ubiquitination (3334353637 ), 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 (3839 ).

FIGURE 1.

Diagram of MHC class I assembly and transport (123 ). MHC class I H chain and β2m assemble with peptide in a multimeric complex with 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 (45678910111213141516 ). 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 (17181920212223242526 ). 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 (2728 ). 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 (2729303132 ). Some virus proteins facilitate the endocytosis of MHC class I molecules by ubiquitination (3334353637 ), 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 (3839 ).

Close modal
Table I.

Selected viral proteins that interfere with Ag presentation

MechanismVirusProtein
Down-regulates MHC class I and β2m transcription HIV-1 Tat 
Reduces the MHC class I mRNA level Bovine papillomavirus E5 
Inhibits phagocytosis by DCsa and thereby interferes with cross-presentation, but also induces DC maturation and surface MHC class I up-regulation HIV-1 Secreted Tat 
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 β2m and peptide HCMV UL18 
Reduced level lessens the availability of epitopes from other viral proteins HIV-1 Rev 
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 
Blocks the transport of MHC class I molecules from the ER into the Golgi MCMV gp40 (m152 product) 
Lowers the surface level of MHC class I by facilitating MHC class I/APLP-2 interaction Adenovirus E3/19K 
Reduces the quantity of MHC class I protein Bovine papillomavirus E5 
Binds MHC class I in the assembly complex and causes rapid turnover of MHC class I Murine γ-herpesvirus 68 mK3 
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 lysosomes 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 an allele-specific mechanism HIV-1 Nef 
Facilitates MHC class I endocytosis by ubiquitination KSHVa K3 and K5 
Complexes with MHC class I in the ER and remains associated with it at the cell surface MCMV gp34 (m04 product) 
MechanismVirusProtein
Down-regulates MHC class I and β2m transcription HIV-1 Tat 
Reduces the MHC class I mRNA level Bovine papillomavirus E5 
Inhibits phagocytosis by DCsa and thereby interferes with cross-presentation, but also induces DC maturation and surface MHC class I up-regulation HIV-1 Secreted Tat 
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 β2m and peptide HCMV UL18 
Reduced level lessens the availability of epitopes from other viral proteins HIV-1 Rev 
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 
Blocks the transport of MHC class I molecules from the ER into the Golgi MCMV gp40 (m152 product) 
Lowers the surface level of MHC class I by facilitating MHC class I/APLP-2 interaction Adenovirus E3/19K 
Reduces the quantity of MHC class I protein Bovine papillomavirus E5 
Binds MHC class I in the assembly complex and causes rapid turnover of MHC class I Murine γ-herpesvirus 68 mK3 
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 lysosomes 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 an allele-specific mechanism HIV-1 Nef 
Facilitates MHC class I endocytosis by ubiquitination KSHVa K3 and K5 
Complexes with MHC class I in the ER and remains associated with it at the cell surface MCMV gp34 (m04 product) 
a

DC, Dendritic cell; KSHV, Kaposi’s sarcoma-associated herpesvirus.

Considering the relatively small size of the HIV-1 genome, a sizable number of HIV-1 gene products have been implicated in interference with MHC class I Ag presentation. The strongest evidence is for roles for Nef and Tat in this process. Nef is a protein that is unnecessary for HIV-1 replication, but that is required for the development of the immune deficiencies associated with HIV infection (40). Nef increases the pathogenicity of HIV in several ways, including down-modulation of cell surface MHC class I molecules (28, 30). Specific regions of Nef that are involved in MHC class I down-regulation have been identified (29, 41). CTL killing of HIV-1-infected primary cells is inefficient if Nef is expressed, and the resistance of the infected cells is due to MHC class I down-regulation (42).

To reduce MHC class I surface expression, Nef and phosphofurin acidic cluster sorting protein-1 cooperate to cause the endocytosis of MHC class I molecules by the ARF6 pathway, and the MHC molecules are recycled into the trans-Golgi network via a process dependent on phosphoinositide 3-kinase (31, 32, 43). However, the effect of Nef on HLA-A2 expressed in T lymphocytes is predominantly inhibition of transport to the surface, rather than facilitation of endocytosis (10). The mechanism of MHC down-modulation may be MHC allele dependent and/or cell dependent (10). For example, the degree of MHC class I cell surface reduction by Nef varies ∼100-fold depending on the type of cell examined (28, 30, 42, 44), suggesting the involvement of cell-specific factors that either assist or interfere with Nef’s activity.

An interesting feature of Nef’s effect on MHC class I is its sequence specificity. For example, HIV-1 down-regulates HLA-A and -B but has little impact on the expression of HLA-C and -E; this selectivity allows HIV-1-infected cells to escape lysis by NK cells (45). Physical interaction has been demonstrated between Nef and particular amino acid residues present in the cytoplasmic tail of HLA-A2, but not in HLA-E and in site-directed HLA-A2 mutants (27). Importantly, the identification of specific binding sites for Nef on MHC molecules may lead to an understanding of differences in AIDS susceptibility or resistance that are linked to particular MHC alleles. In contrast to its effect on HLA-A2, Nef has very little effect on murine MHC class I molecules (46), a finding that further adds to our appreciation of the difficulty of deriving a suitable small-animal model for AIDS. Studies with mouse/human MHC chimeras indicate that amino acid residues in the extracellular domains of the MHC molecule, as well as in the cytoplasmic domain, can play a role in Nef-mediated MHC class I down-modulation (46).

The HIV-1 tat gene encodes a protein that transactivates HIV transcription (47). Tat is able to repress MHC class I promoter activity, as well as the activity of the promoter for β2m (48, 49, 50, 51). Tat is also capable of inhibiting the association of the 11S regulator subunit with the proteasome via a shared binding site, interfering with the production of peptides for MHC binding (17, 18). Tat is also secreted by HIV-infected cells (52). The presence of extracellular HIV-1 Tat indirectly affects MHC class I presentation by inhibiting dendritic cell phagocytosis of apoptosed cells (53, 54). However, Tat’s effects on dendritic cells are complex. Recently, it was reported that Tat is efficiently taken up by dendritic cells by a process that seems to involve receptor-mediated endocytosis (55). Once internalized, Tat induces dendritic cell maturation and thereby, in an interesting twist to the Tat story, causes up-regulation of cell surface MHC class I (as well as MHC class II and costimulatory molecules) (55).

In addition to the effects of Nef and Tat, there are also hints that HIV-1 Vpu may increase the turnover rate of nascent MHC class I H chains (14), and that an as-yet-unidentified HIV-1 protein may block TAP transport of peptides into the ER (21). Furthermore, HIV-1 Rev has recently been shown to influence MHC class I Ag presentation by an indirect mechanism (56). The Rev protein assists in the transport of certain other HIV-1 mRNAs, and so it is necessary for the expression of these other HIV-1 proteins (Gag, Pol, and Env). Asymptomatic HIV-1 carriers tend to have low Rev activity and therefore low Gag expression, leading to ineffective killing of infected cells by CTL specific for Gag epitopes. Notably, such an observation underscores the importance of not restricting studies of MHC/virus interaction to the examination of the effect of a single virus protein in isolation.

The human pathogen Kaposi’s sarcoma-associated herpesvirus encodes two gene products, K3 and K5, that are able to reduce drastically the number of MHC class I molecules at the cell surface by facilitating their endocytosis (33, 34, 57). The mechanism for this effect has been demonstrated to be ubiquitination of the MHC class I H chain (or a protein associated with it), and the effect can be blocked by protease inhibition (35, 36). Separate motifs within the K3 protein are responsible for the endocytosis of MHC class I molecules and for targeting them for lysosomal degradation in a tumor susceptibility gene 101-dependent sorting process (37, 38). A related virus that is a horse pathogen, equine herpesvirus-1, has likewise been shown to cause endocytosis of cell surface MHC class I molecules (58).

Another herpesvirus, murine γ-herpesvirus 68, encodes a K3 protein (mK3) that induces rapid turnover of MHC class I molecules by a mechanism not involving endocytosis (12, 13, 57). The mK3 protein has been demonstrated to assist the virus in escape from T cells during the latent phase of infection (59). The activity of mK3 initiates the effective degradation of most murine MHC class I allele products, but there are exceptions, which may be due to differences in trafficking rate or sequence among different MHC class I molecules (12). MHC class I molecules in assembly complexes awaiting peptides are preferentially associated with mK3 (12), and, in fact, the assembly complex proteins TAP and tapasin are absolutely required for mK3’s effect on MHC class I (60). The absence of TAP or tapasin, or MHC class I mutations abrogating interaction with TAP and tapasin, prevent mK3 from binding to MHC class I and down-regulating its surface expression (60).

An ER-resident protein that can cause down-regulation of surface MHC class I is also expressed by myxoma virus, which is a poxvirus rather than a herpesvirus (61). A unifying characteristic of this myxoma protein, the Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins, and the murine γ-herpesvirus 68 mK3 proteins is that they all possess a particular type of conserved structural motif that is correlated with ubiquitin ligase activity. Indeed, the myxomavirus M153R protein has been shown to have ubiquitin ligase activity in vitro, and MHC class I cytoplasmic tail lysines are necessary for down-regulation of the MHC class I molecules by M153R (39). This characteristic sequence motif is also apparent in several other herpesviruses and poxviruses (61), raising the possibility that more viruses may be identified in the future as capable of interfering with peptide presentation by this same mechanism.

Murine CMV (MCMV) expresses three genes that encode protein for blocking Ag presentation: m04, m06, and m152. By use of a set of mutant MCMVs with deletions of the three genes in all possible permutations, the effect on the surface expression of multiple MHC class I allele products was examined (62). These experiments showed that these MCMV proteins can have synergistic effects, but certain combinations of these proteins are actually antagonistic; thus, this approach revealed a truer picture of MCMV’s effects on MHC class I in the course of natural infection than had been hitherto obtained.

Although there is substantial evidence for an MCMV gene, m152, affecting the presentation of a particular MCMV epitope in vitro, the immunodominance of the same epitope in vivo is not affected by whether m152 is expressed (63). Thus, the effect of MCMV proteins on cells that endogenously express them and their effect on professional APCs that take them up and present their peptides by cross-priming appear to be distinct. The impact of MCMV infection on APCs has also been examined in other recent studies. The results from these studies indicate that MCMV does induce down-regulation of MHC molecules on dendritic cells and macrophages; however, there are differences in the effects of immune evasion genes when APCs and fibroblasts are compared (64, 65, 66). For example, expression of the m04, m06, and m152 genes are all necessary to block recognition of macrophages by Kb-restricted CTLs, and the m04 gene, in particular, plays a greater role in inhibition of T cell recognition in macrophages than in fibroblasts (66).

Human CMV (HCMV) invests heavily in products able to interfere with MHC class I. The HCMV unique short (US) genes (US2, US3, US6, and US11) all assist HCMV in evading MHC class I presentation. HCMV encodes a unique long (UL) region protein, UL18, which is an MHC class I homolog, capable of binding β2m and peptide (67, 68, 69). Notably, the surface expression of UL18 is not affected by US2, US3, US6, or US11, indicating that all of these US proteins accurately discern sequence differences between multiple host-encoded MHC molecules and the HCMV-encoded imitator (70).

HCMV US2 (and US11) cause ejection of MHC class I H chains into the cytoplasm, which results in their proteasomal degradation (15, 16). The US2 cytoplasmic domain has been shown to have major involvement in this process (71, 72). Although studies in cultured cell lines did not distinguish US2 and US11 in effectiveness, new experiments with primary human dendritic cells have revealed that US11 is much more effective than US2 at degrading MHC class I in these cells (73). US3 possesses a novel, noncontiguous ER retention sequence, and binds to MHC class I to prevent its egress to the cell surface (4, 5, 74). US6 inhibits TAP, thereby blocking peptide loading of HLA-A, -B, and -C molecules, but not HLA-E; this preservation of HLA-E expression ensures protection against NK cells (22, 23, 24, 75). Inhibition of TAP has been used successfully as a defensive mechanism by other herpesviruses, including a swine pathogen, pseudorabies (25), and bovine herpesvirus 1 (26, 76).

Another HCMV US gene product, US8, has recently been discovered to bind MHC class I molecules in the ER (77). US8 does not quantitatively affect MHC class I surface expression (77), although its influence on MHC class I-restricted Ag presentation remains to be more fully explored. In contrast, another US product, US10, has recently been found to delay the migration of folded MHC class I molecules out of the ER, reminiscent of US3 (6).

The adenoviral protein E3/19K was first shown to down-regulate cell surface MHC class I expression by direct retention of MHC H chains in the ER (7, 8). Later, it was demonstrated that E3/19K also binds to TAP, apart from its direct interaction with the MHC molecule (19). As a result of binding to TAP, E3/19K blocks the association of TAP with tapasin (19). Recently, it was found that the E3/19K protein binds preferentially to the folded form of the MHC class I molecule, as does the ubiquitous cellular protein amyloid precursor-like protein 2 (APLP2) (9). APLP2 is a type I transmembrane protein and a member of the amyloid precursor protein family (78). APLP2 reduces the number of MHC class I molecules that reach the cell surface, and E3/19K significantly increases the association of MHC class I with APLP2 (9, 79). Thus, by facilitating MHC binding to APLP2, E3/19K can act via APLP2 to inhibit MHC surface expression. In total, a single adenovirus protein, E3/19K, can attack MHC class I by three separate mechanisms, serving as a highly resourceful viral weapon against the cellular immune response.

Cellular transformation by adenovirus type 12 (Ad12) induces an oncogenic phenotype (80). One apparent aspect of this phenotype is the reduction in surface MHC class I molecules that accompanies Ad12 transformation, allowing escape from T cell lysis (81). Relevant to surface down-regulation of MHC class I, Ad12-transformed cells have decreased expression of the MHC H chain, TAP, tapasin, LMP-2, LMP-7, MECL-1, and PA28 (20, 82, 83). Reduced expression of these proteins has been attributed to an IFN-related effect (84, 85), and, in the case of MHC class I transcriptional down-regulation, dual mechanisms (i.e., repressive COUP-TFII and inactivated NF-κB) are used, evidently as mutual back-up measures (86).

Two reports in the last year have indicated that the bovine papillomavirus E5 protein can down-regulate the surface expression of MHC class I molecules (87, 88). Cells that express E5 have reduced levels of MHC class I mRNA and protein and surface MHC class I, whereas surface expression of a control protein, the transferrin receptor, is not affected (87). E5 can retain MHC class I in multiple cell types (87), and the site of blockade has been shown to be the Golgi (88). Because E5 is a viral oncoprotein, this finding is of interest from the perspective of tumor, as well as virus, escape from the specific immune response.

An important new trend in the analysis of MHC class I/virus interactions, evidenced by several of the studies described above, is the rising frequency of productive investigation of these interactions in the context of virus infection, using gene-deletion virus variants and samples from infected patients. The results obtained with these approaches are providing us an appreciation of complementary and antagonistic interactions among the proteins expressed by each virus. Certainly, a future generation of these studies will involve analysis of the impact on MHC class I Ag presentation of infections with multiple different chronic viruses, as is often the case in the human situation.

The effects of viruses on MHC class I function are also being analyzed in recent studies in a wider variety of cell types than ever before, including professional APCs. In addition to HIV and MCMV, other viruses, e.g., human herpesvirus 3 (also known as varicella-zoster virus), infect dendritic cells and down-regulate expression of MHC class I molecules on them (89). Taken together, the findings with APCs suggest that viruses can affect presentation of peptides in these cells, and, in addition, that there are many functionally important nuances of viral immune evasion to be discovered when APCs are compared with other cell types.

Although the selective pressure on viruses to down-regulate MHC class I expression for the purpose of avoiding CTL killing is apparent, the ability of viruses to escape from CTLs without simultaneously increasing susceptibility to NK cells is intriguing. Several recent studies have dealt with this issue, and in the process have generated a new immunology subfield: virus interference with NK cell recognition. In one case, the host has turned the virus’s weapon on itself. In a story replete with evolutionary twists, a cell surface MCMV protein encoded by m157 binds to an inhibitory NK cell receptor that is expressed by an MCMV-susceptible mouse strain, and the same m157 product binds to an activating NK cell receptor in MCMV-resistant mice (90).

In many cases, the new findings in this area involve viral proteins that down-regulate MHC class I as well as NK recognition. For example, the m152 gene product of MCMV, which inhibits the MHC class I expression, also affects NK cell reactivity against MCMV by modulation of NKG2D ligands, specifically retinoic acid early inducible 1 proteins (11, 91, 92, 93). The Kaposi’s sarcoma-associated herpesvirus K5 protein, which down-regulates MHC class I surface expression, also down-regulates the expression of ICAM-1 and B7-2 molecules and thereby inhibits lysis by NK cells (94). In other cases, viral proteins that block NK activity interact with MHC-like molecules. An HCMV protein (UL16) interferes with the recognition of activating NKG2 receptors on NK cells by binding to the MHC class I-related molecules that serve as the ligands for these activating receptors (95). Thus, the viral defense strategies against CTLs and NK cells are intertwined, in a fabric that is fascinating to unravel.

In summary, publications from many laboratories indicate that much more has been recently learned about how viruses defend against MHC class I presentation. These viral defense mechanisms are not without price, because it has also been discovered that expression of immune evasion proteins can permit the host to present and recognize peptides from those same proteins (96, 97). Nevertheless, the existence and prevalence of viruses that express such proteins indicate that the outcome is indeed worth the cost.

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.).

3

Abbreviations used in this paper: β2m, β2-microglobulin; ER, endoplasmic reticulum; TAP, transporter associated with Ag processing; MCMV, murine CMV; HCMV, human CMV; US, unique short; UL, unique long; APLP2, amyloid precursor-like protein 2; Ad12, adenovirus type 12.

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