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Viral effects on antigen processing
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Viral effects on antigen processing Daniel M Miller and Daniel D Sedmak* Viruses have evolved numerous mechanisms that modulate MHC-mediated antigen presentation, which in turn protect infected cells from T-lymphocyte-mediated immunosurveillance. Recent studies of previously identified viral immunomodulatory proteins reveal the allelic specificity of these proteins, their ability to function in xenogeneic systems and the difficulty in translating in vitro data to in vivo models; moreover, new mechanisms of viral modulation of MHC expression have emerged. Addresses Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA *e-mail: [email protected] Correspondence: Daniel D Sedmak Current Opinion in Immunology 1999, 11:94–99 http://biomednet.com/elecref/0952791501100094 © Elsevier Science Ltd ISSN 0952-7915 Abbreviations AP adaptor protein CLIP class-II-associated Ii-chain peptide EBNA EBV nuclear antigen EBV Epstein–Barr virus ER endoplasmic reticulum HCMV human cytomegalovirus HSV herpes simplex virus ICP47 infected cell protein 47 IFN interferon JAK Janus kinase LFA-3 lymphocyte function-associated antigen 3 LIR-1 leukocyte immunoglobulin-like receptor 1 MCMV murine cytomegalovirus NK natural killer STAT signal transducer and activator of transcription TAP transporter associated with antigen processing
Introduction Many viruses are capable of establishing persistent infections in mammalian hosts. In human hosts, persistent viruses — such as herpesviruses, adenoviruses, retroviruses and papillomaviruses — are responsible for significant, and world-wide, morbidity and mortality. It is critical for our understanding of the pathobiology of persistent viruses to uncover the mechanisms by which they protect themselves from innate and adaptive immunity. The MHC is the ultimate interface between the virus and the adaptive immune system. CD8+ and CD4+ T lymphocytes recognize peptides that are derived from viral proteins; this recognition occurs in the context of MHC class I and class II, respectively. Once this occurs, virus-specific CD8+ and CD4+ T lymphocytes proliferate and they may lyse virally infected cells or release cytokines that inhibit viral replication and that activate the immune system. A major component of viral persistence is the ability to prevent efficient presentation of virally derived peptides in the context of MHC class I and class II molecules.
By investigating the mechanisms of viral persistence and pathobiology, novel antiviral targets are uncovered and invaluable tools for the study of antigen presentation, autoimmunity, vaccine design, gene therapy and transplantation are isolated. Herein, we will focus on findings — on viral inhibition of MHC class I and class II antigen presentation, lytic activity of natural killer (NK) cells and cytokine modulation of MHC expression — that have emerged since the previous review [1].
Viral inhibition of MHC class I antigen presentation MHC class I molecules are heterodimeric molecules consisting of a transmembrane glycoprotein heavy chain and a soluble β2-microglobulin light chain. The generation of peptides for the class I pathway largely occurs by proteasome-mediated degradation of cytosolic proteins [2]. The transporter associated with antigen processing (TAP) translocates peptides of 8–12 amino acids from the cytosol into the endoplasmic reticulum (ER) [2]. ER-resident chaperones, such as calnexin, facilitate the folding of class I heavy chains and the loading of free peptides onto the class I binding cleft [2]. Peptide-loaded MHC class I molecules traffic through the Golgi apparatus to the cell surface where they display virally derived peptide to CD8+ T lymphocytes. Two members of the herpesvirus family inhibit the first step in MHC class I antigen presentation — proteolysis of cytosolic proteins (Figure 1). The human cytomegalovirus (HCMV) virion matrix protein pp65 appears to phosphorylate the HCMV IE proteins and may prevent their processing by the proteasome, thereby evading recognition by cytotoxic T cells [3]. Similarly, the Epstein–Barr virus (EBV) EBNA (EBV nuclear antigen)-1 protein contains a Gly–Ala repeat domain that inhibits antigen processing by the proteasome [4]. Another viral target in the MHC class I pathway is the TAP complex (Figure 1). The HCMV US6 protein, a type I membrane glycoprotein, binds the TAP complex within the ER lumen and inhibits its peptide-transporting function [5,6]. Herpes simplex virus (HSV) encodes a cytosolic protein, infected cell protein 47 (ICP47), which binds via its amino-terminus to the cytosolic peptide-binding domain of TAP and prevents peptide binding — resulting in ‘empty’ MHC class I molecules [7,8,9•]. In vitro studies investigating ICP47-mediated TAP blocking activity in a variety of animal species demonstrate that ICP47 blocks TAP activity in human, pig, dog, cow and monkey cells whereas mouse, rat, guinea pig and rabbit cells are relatively resistant to this blockage [10•,11]; however experiments utilizing an HSV-1 ICP47 deletion mutant in a murine ocular model demonstrate a striking
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Figure 1
Stimulatory cytokine (e.g. IFN-γ)
Intact proteins
ER JAK/STAT pathway
(a) HCMV MCMV E1A
Nucleus
Cell surface (b) pp65 EBNA-1 Proteasome Antigenic peptide Degradation (c) US6 US2 ICP47 US11 IL-10 homolog Vpu TAP US3 m152 E3-19K (d)
Trans Golgi
Cis Golgi
Surface expression
Nef
(f)
MHC class I Gene transcription
MHC class II
(e) E6
Antigenic peptide Endosomal– lysosomal compartment
Current Opinion in Immunology
Viral gene products block the MHC antigen-presentation pathway at multiple levels. Viruses, or their products, may (a) block stimulatory cytokine responses (e.g. IFN-γ-mediated JAK/STAT signaling). (b) Some viruses block the initial step in the MHC class I pathway — proteolysis of cytosolic proteins by the proteasome. (c) Two members of the herpesvirus family encode proteins (US6 and ICP47) that block
TAP-mediated transport of peptides into the ER. An EBV IL-10 homolog downregulates TAP expression. (d), (e), (f) Numerous viral gene products alter the trafficking of MHC class I and class II molecules in the ER, or in the Golgi or endocytic (endosomal–lysosomal) compartments.
role for ICP47 in HSV neurovirulence [12••], highlighting the difficulty in extrapolating in vitro data to in vivo models. HSV-infected mice die of encephalitis whereas mice infected with ICP47-negative HSV show little or no neurologic symptoms or disease [12 ••]; moreover, ICP47-negative virus exhibits neurovirulence similar to wild-type virus when mice are depleted of CD8+ T lymphocytes, supporting the conclusion that ICP47 blocks class-I-restricted recognition of infected nervous tissue by CD8+ T lymphocytes [12••]. Thus although ICP47 binds poorly to mouse TAP (as compared to human TAP), tissuespecific factors such as lower constitutive levels of MHC class I molecules can dramatically enhance the ability of a viral protein such as ICP47 to inhibit antigen presentation.
within the ER [15,16]. The HCMV US2 and US11 glycoproteins mediate reverse translocation of MHC class I heavy chains from the ER through the Sec61 complex to the cytoplasm, where the heavy chains are deglycosylated by host N-glycanase and are rapidly degraded by the proteasome [17]. US2 and US11 are expressed at the same time after infection and the advantage of a virus simultaneously expressing two proteins with similar functions is not immediately clear. One hypothesis for the overlapping kinetics and function of these proteins is that they target distinct MHC class I alleles. In fact, a recent study demonstrates that US11 degrades mouse H2-Kb, -Kd, -Db, -Dd and -Ld alleles whereas US2 degrades H2-Db and -Dd [18•].
MHC class I trafficking and surface expression is also directly targeted (Figure 1). E3-19K glycoproteins — from adenovirus groups B, C, D, E and F — bind and retain MHC class I heavy chains in the ER, preventing the transport of heavy chains to the cell surface [13,14]. Similarly, products of the HCMV US3 and the murine cytomegalovirus (MCMV) m152 genes mediate the retention of MHC class I molecules
Structural differences between human class I heavy chain alleles affect their sensitivity to the degradation that is mediated by US2 and US11. For example, the human HLA-C and HLA-G class I products are resistant to the effects of US2 and US11 in human trophoblasts [19•]. US2 and US11 also function in xenogeneic cells, as evidenced by their targeting of HLA-A2 for degradation in porcine
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endothelial cells [19•]. These findings suggest that US2 and US11 may be valuable in animal models of autoimmunity and transplantation. The HIV-1 proteins, Vpu and Nef, have also been shown to decrease MHC class I expression. Vpu induces the rapid loss of class I heavy chains in the ER of peripheral blood leukocytes that are depleted of CD8+ cells [20•]. This may be secondary to the translocation of heavy chains from the ER to cytosol for proteasome-mediated destruction in a manner similar to HCMV US2 and US11. Recent investigations have shown that HIV-1 Nef downregulates MHC class I complexes by a novel mechanism involving the accumulation of endocytosed MHC class I molecules in the trans-Golgi, in which Nef colocalizes with the adaptor protein (AP)-1 complex [21•]. This downregulation has been confirmed in primary T lymphocytes, where Nef mediates up to a 300-fold reduction of surface MHC class I expression with subsequent protection from recognition by HIV-specific cytotoxic T lymphocytes [22••]; moreover Nef appears to have broad allelic specificity — it downregulates HLA-A2, -A3, -B7, -B51 and an HLA-C allele [22••]. Nef also has the ability to colocalize with AP-2 and downregulate CD4 expression [23].
Viral modulation of NK cell activity Cells that are negative for MHC class I are classic targets of NK cells; therefore, virally-infected cells with reduced MHC class I surface expression are inherently susceptible to attack from NK cells; however, there is evidence that HCMV may have evolved a strategy to protect infected cells that have little or no surface class I from lysis by NK cells. Studies utilizing HCMV-infected endothelial cells that lack surface MHC class I have shown that such cells demonstrate a marked resistance to lysis by allogeneic NK cells [24•]. The HCMV UL18 and the MCMV m144 genes encode an MHC class I homolog that binds β2-microglobulin and is expressed on the cell surface [25,26]. Studies have suggested that these molecules engage inhibitory MHC class I receptors on NK cells, thus protecting infected cells from NK lysis [27]; however, experiments with UL18-knockout virus and with cell lines transfected with the UL18 gene have demonstrated enhanced NK cell killing of UL18+ targets [28••]. Recent findings also indicate that UL18 binds to a novel immunoglobulin superfamily glycoprotein — leukocyte immunoglobulin-like receptor 1 (LIR-1), an inhibitory receptor expressed on monocytes and B cells but on only a minor subset of NK cells [29••]. It has been suggested that UL18 on HCMV-infected cells interacts with LIR-1 on monocytes and suppresses IL-12 production, thereby limiting IL-12-mediated IFN-γ secretion by NK cells [29••]. Analysis of laboratory-propagated HCMV strains and clinical isolates, all of which cause a marked decrease in MHC class I expression, reveals a differential pattern of sensitivity to lysis by NK cells. It appears that cytotoxicity
correlates best with increased surface expression of the adhesion molecule LFA-3 (lymphocyte function-associated antigen 3); the cytotoxicity may result from LFA-3 interaction with CD2 molecules on NK cells [30•]. In summary, subsets of virally infected cells may be able to escape lysis that is mediated by NK cells; however, the molecules and mechanisms responsible for this phenomenon remain controversial and elusive.
Viral inhibition of MHC class II antigen presentation The MHC class II system presents peptides generated in the endosomal–lysosomal system [31]. MHC class II molecules consist of a heterodimer of transmembrane glycoprotein subunits, α and β. In the ER, three MHC class II α and β dimers combine with a homotrimeric invariant chain (termed Ii) forming a nonameric complex [31]. The complex of class II and Ii chains trafficks through the Golgi apparatus, where targeting signals in the cytoplasmic domain of Ii direct the complex to endosomal–lysosomal compartments [31]. In these compartments, proteolysis of the Ii chain produces the class-II-associated Ii-chain peptide (CLIP); this may bind to released class II dimers [31]. Complexes of class I and CLIP traffic to a specialized lysosome-like compartment (the MHC class II compartment) where HLA-DM facilitates the displacement of CLIP molecules with lysosomal peptides in the peptide-binding groove of class II molecules. Peptide-loaded MHC class II molecules move to the cell surface where they present antigen to CD4+ T lymphocytes. CD4+ T lymphocytes are important in controlling viral infections [32]. They secrete cytokines that augment CD8+ T lymphocyte and B lymphocyte responses and that directly inhibit viral replication [33]; moreover, subsets of CD4+ T lymphocytes are capable of lysing virally infected cells in a class-II-restricted fashion [34]. One target of viruses in thwarting antigen presentation by MHC class II may be the trafficking of MHC class II molecules (Figure 1). Studies in HCMV-infected monocyte-derived macrophages demonstrate reduced surface expression of MHC class II, which may result from impaired class II trafficking [35]. A candidate bovine papillomavirus molecule for inhibiting class II trafficking is the E6 protein, which binds to the AP-1 complex that is specific for the trans-Golgi network; this complex is necessary for vesicular trafficking [36•]. MHC class II is constitutively expressed on professional antigen-presenting cells, such as monocytes and B cells, but is upregulated in response to cytokines such as IFN-γ on many other cell types [37]. Recently, experiments have shown that HCMV blocks IFN-γ-stimulated MHC class II expression in human fibroblasts and endothelial cells [38]. The block in IFN-γ-stimulated MHC class II
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Table 1 Effects of viruses on antigen presentation. Effect
Virus
Gene name/product
Mechanism
Adenovirus HCMV MCMV EBV
E1A ? ? BCRF1
Blocks JAK/STAT signal transduction Blocks JAK/STAT signal transduction Inhibits IFN-γ-stimulated MHC class II expression Viral IL-10 homologue; decreases TAP1 expression
HCMV EBV
pp65 EBNA-1
Prevents processing of IE proteins Gly—Ala repeat domain blocks proteasomemediated processing
HSV HCMV
ICP47 US6
Adenovirus HCMV MCMV HCMV
E3-19K US3 m152 US2, US11
HIV
Nef
HIV HCMV BPV
Vpu ? E6
HCMV
UL18
MCMV
m144
Cytokine modulation of antigen presentation
Inhibition of antigen processing
Inhibition of TAP Blocks TAP activity by binding to cytosolic surface of TAP Transmembrane glycoprotein inhibits TAP from within ER lumen
Decrease of MHC trafficking and expression Retains MHC class I molecules in ER Retains MHC class I molecules in ER Retains MHC class I molecules in ER Reverse movement of class I heavy chain from ER to cytoplasm for degradation Accumulation of endocytosed MHC class I molecules in the trans-Golgi, colocalizes with AP-1 complex Degrades MHC class I? Decreases MHC class II in monocytes? Binds AP-1, possibly inhibits trafficking of MHC class II molecules
Expression of viral immunomodulatory molecules Enhances cytolysis by NK cells? Interacts with LIR-1 to inhibit monocyte and B cell activation? Effects on NK cells or monocytes?
BPV, bovine papillomavirus.
expression occurs at the level of IFN-γ-stimulated JAK/STAT (Janus kinase/signal transducer and activator of transcription) signal transduction [39•]. In MCMV-infected bone marrow macrophages, IFN-γstimulated MHC class II expression is also inhibited but by a mechanism not involving IFN-γ-stimulated signal transduction [40•]. The HCMV and MCMV gene products mediating these effects remain to be identified.
Viral inhibition of cytokine-mediated upregulation of MHC antigen presentation Cytokines, particularly the type I and II IFNs, are potent stimulators of antigen processing and MHC expression. IFNs upregulate the transcription of MHC molecules and associated antigen-processing proteins such as the Ii chain, HLA-DM, TAP and proteasome subunits [37,41]. It is as a result of transcriptional control that expression of MHC class I and class II molecules varies between tissues in vivo [42–45]. Several viruses have evolved mechanisms for inhibiting IFN-stimulated MHC expression [46]. Specifically, the adenovirus E1A protein inhibits cellular responses — stimulated by IFN-α and IFN-γ — at the level of JAK/STAT signal
transduction by decreasing STAT1 and p48 expression [47,48]. In an analogous fashion, HCMV inhibits MHC class I and II expression — stimulated by IFN-α and IFN-γ — at the level of JAK/STAT signal transduction by decreasing JAK1 and p48 expression ([39•]; DM Miller, unpublished data). In murine macrophages, MCMV inhibits IFN-γ-stimulated MHC class II expression [40•]. Alternatively, viruses may encode molecules that mimic the action of inhibitory cytokines. EBV encodes an IL-10 homolog which is capable of downregulating TAP1 expression thereby limiting MHC class I antigen presentation [49].
Conclusions Viruses have developed protean means of blocking antigen presentation (Table 1). It is probable that these molecules have arisen from the selective pressures exerted by mammalian immune systems on persistent viruses during their millions of years of coevolution. The resulting viral molecules are highly specific and efficient at blocking multiple levels of antigen processing. In-depth knowledge of their structure and function will lead to a greater understanding of viral persistence and of the
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function of the immune system. These molecules may also prove to be of great value in gene therapy, vaccine design, autoimmunity and transplantation.
14. Sester M, Burgert HG: Conserved cysteine residues within the E3/19K protein of adenovirus type 2 are essential for binding to major histocompatibility complex antigens. J Virol 1994, 68:5423-5432.
Acknowledgements
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The authors are supported by National Institutes of Health grant AI38452-01A1. Daniel Miller was a Howard Hughes Medical Institute Postdoctoral Fellow.
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Viral effects on antigen processing Daniel M Miller and Daniel D Sedmak* Viruses have evolved numerous mechanisms that modulate MHC-mediated antigen presentation, which in turn protect infected cells from T-lymphocyte-mediated immunosurveillance. Recent studies of previously identified viral immunomodulatory proteins reveal the allelic specificity of these proteins, their ability to function in xenogeneic systems and the difficulty in translating in vitro data to in vivo models; moreover, new mechanisms of viral modulation of MHC expression have emerged. Addresses Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA *e-mail: [email protected] Correspondence: Daniel D Sedmak Current Opinion in Immunology 1999, 11:94–99 http://biomednet.com/elecref/0952791501100094 © Elsevier Science Ltd ISSN 0952-7915 Abbreviations AP adaptor protein CLIP class-II-associated Ii-chain peptide EBNA EBV nuclear antigen EBV Epstein–Barr virus ER endoplasmic reticulum HCMV human cytomegalovirus HSV herpes simplex virus ICP47 infected cell protein 47 IFN interferon JAK Janus kinase LFA-3 lymphocyte function-associated antigen 3 LIR-1 leukocyte immunoglobulin-like receptor 1 MCMV murine cytomegalovirus NK natural killer STAT signal transducer and activator of transcription TAP transporter associated with antigen processing
Introduction Many viruses are capable of establishing persistent infections in mammalian hosts. In human hosts, persistent viruses — such as herpesviruses, adenoviruses, retroviruses and papillomaviruses — are responsible for significant, and world-wide, morbidity and mortality. It is critical for our understanding of the pathobiology of persistent viruses to uncover the mechanisms by which they protect themselves from innate and adaptive immunity. The MHC is the ultimate interface between the virus and the adaptive immune system. CD8+ and CD4+ T lymphocytes recognize peptides that are derived from viral proteins; this recognition occurs in the context of MHC class I and class II, respectively. Once this occurs, virus-specific CD8+ and CD4+ T lymphocytes proliferate and they may lyse virally infected cells or release cytokines that inhibit viral replication and that activate the immune system. A major component of viral persistence is the ability to prevent efficient presentation of virally derived peptides in the context of MHC class I and class II molecules.
By investigating the mechanisms of viral persistence and pathobiology, novel antiviral targets are uncovered and invaluable tools for the study of antigen presentation, autoimmunity, vaccine design, gene therapy and transplantation are isolated. Herein, we will focus on findings — on viral inhibition of MHC class I and class II antigen presentation, lytic activity of natural killer (NK) cells and cytokine modulation of MHC expression — that have emerged since the previous review [1].
Viral inhibition of MHC class I antigen presentation MHC class I molecules are heterodimeric molecules consisting of a transmembrane glycoprotein heavy chain and a soluble β2-microglobulin light chain. The generation of peptides for the class I pathway largely occurs by proteasome-mediated degradation of cytosolic proteins [2]. The transporter associated with antigen processing (TAP) translocates peptides of 8–12 amino acids from the cytosol into the endoplasmic reticulum (ER) [2]. ER-resident chaperones, such as calnexin, facilitate the folding of class I heavy chains and the loading of free peptides onto the class I binding cleft [2]. Peptide-loaded MHC class I molecules traffic through the Golgi apparatus to the cell surface where they display virally derived peptide to CD8+ T lymphocytes. Two members of the herpesvirus family inhibit the first step in MHC class I antigen presentation — proteolysis of cytosolic proteins (Figure 1). The human cytomegalovirus (HCMV) virion matrix protein pp65 appears to phosphorylate the HCMV IE proteins and may prevent their processing by the proteasome, thereby evading recognition by cytotoxic T cells [3]. Similarly, the Epstein–Barr virus (EBV) EBNA (EBV nuclear antigen)-1 protein contains a Gly–Ala repeat domain that inhibits antigen processing by the proteasome [4]. Another viral target in the MHC class I pathway is the TAP complex (Figure 1). The HCMV US6 protein, a type I membrane glycoprotein, binds the TAP complex within the ER lumen and inhibits its peptide-transporting function [5,6]. Herpes simplex virus (HSV) encodes a cytosolic protein, infected cell protein 47 (ICP47), which binds via its amino-terminus to the cytosolic peptide-binding domain of TAP and prevents peptide binding — resulting in ‘empty’ MHC class I molecules [7,8,9•]. In vitro studies investigating ICP47-mediated TAP blocking activity in a variety of animal species demonstrate that ICP47 blocks TAP activity in human, pig, dog, cow and monkey cells whereas mouse, rat, guinea pig and rabbit cells are relatively resistant to this blockage [10•,11]; however experiments utilizing an HSV-1 ICP47 deletion mutant in a murine ocular model demonstrate a striking
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Figure 1
Stimulatory cytokine (e.g. IFN-γ)
Intact proteins
ER JAK/STAT pathway
(a) HCMV MCMV E1A
Nucleus
Cell surface (b) pp65 EBNA-1 Proteasome Antigenic peptide Degradation (c) US6 US2 ICP47 US11 IL-10 homolog Vpu TAP US3 m152 E3-19K (d)
Trans Golgi
Cis Golgi
Surface expression
Nef
(f)
MHC class I Gene transcription
MHC class II
(e) E6
Antigenic peptide Endosomal– lysosomal compartment
Current Opinion in Immunology
Viral gene products block the MHC antigen-presentation pathway at multiple levels. Viruses, or their products, may (a) block stimulatory cytokine responses (e.g. IFN-γ-mediated JAK/STAT signaling). (b) Some viruses block the initial step in the MHC class I pathway — proteolysis of cytosolic proteins by the proteasome. (c) Two members of the herpesvirus family encode proteins (US6 and ICP47) that block
TAP-mediated transport of peptides into the ER. An EBV IL-10 homolog downregulates TAP expression. (d), (e), (f) Numerous viral gene products alter the trafficking of MHC class I and class II molecules in the ER, or in the Golgi or endocytic (endosomal–lysosomal) compartments.
role for ICP47 in HSV neurovirulence [12••], highlighting the difficulty in extrapolating in vitro data to in vivo models. HSV-infected mice die of encephalitis whereas mice infected with ICP47-negative HSV show little or no neurologic symptoms or disease [12 ••]; moreover, ICP47-negative virus exhibits neurovirulence similar to wild-type virus when mice are depleted of CD8+ T lymphocytes, supporting the conclusion that ICP47 blocks class-I-restricted recognition of infected nervous tissue by CD8+ T lymphocytes [12••]. Thus although ICP47 binds poorly to mouse TAP (as compared to human TAP), tissuespecific factors such as lower constitutive levels of MHC class I molecules can dramatically enhance the ability of a viral protein such as ICP47 to inhibit antigen presentation.
within the ER [15,16]. The HCMV US2 and US11 glycoproteins mediate reverse translocation of MHC class I heavy chains from the ER through the Sec61 complex to the cytoplasm, where the heavy chains are deglycosylated by host N-glycanase and are rapidly degraded by the proteasome [17]. US2 and US11 are expressed at the same time after infection and the advantage of a virus simultaneously expressing two proteins with similar functions is not immediately clear. One hypothesis for the overlapping kinetics and function of these proteins is that they target distinct MHC class I alleles. In fact, a recent study demonstrates that US11 degrades mouse H2-Kb, -Kd, -Db, -Dd and -Ld alleles whereas US2 degrades H2-Db and -Dd [18•].
MHC class I trafficking and surface expression is also directly targeted (Figure 1). E3-19K glycoproteins — from adenovirus groups B, C, D, E and F — bind and retain MHC class I heavy chains in the ER, preventing the transport of heavy chains to the cell surface [13,14]. Similarly, products of the HCMV US3 and the murine cytomegalovirus (MCMV) m152 genes mediate the retention of MHC class I molecules
Structural differences between human class I heavy chain alleles affect their sensitivity to the degradation that is mediated by US2 and US11. For example, the human HLA-C and HLA-G class I products are resistant to the effects of US2 and US11 in human trophoblasts [19•]. US2 and US11 also function in xenogeneic cells, as evidenced by their targeting of HLA-A2 for degradation in porcine
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endothelial cells [19•]. These findings suggest that US2 and US11 may be valuable in animal models of autoimmunity and transplantation. The HIV-1 proteins, Vpu and Nef, have also been shown to decrease MHC class I expression. Vpu induces the rapid loss of class I heavy chains in the ER of peripheral blood leukocytes that are depleted of CD8+ cells [20•]. This may be secondary to the translocation of heavy chains from the ER to cytosol for proteasome-mediated destruction in a manner similar to HCMV US2 and US11. Recent investigations have shown that HIV-1 Nef downregulates MHC class I complexes by a novel mechanism involving the accumulation of endocytosed MHC class I molecules in the trans-Golgi, in which Nef colocalizes with the adaptor protein (AP)-1 complex [21•]. This downregulation has been confirmed in primary T lymphocytes, where Nef mediates up to a 300-fold reduction of surface MHC class I expression with subsequent protection from recognition by HIV-specific cytotoxic T lymphocytes [22••]; moreover Nef appears to have broad allelic specificity — it downregulates HLA-A2, -A3, -B7, -B51 and an HLA-C allele [22••]. Nef also has the ability to colocalize with AP-2 and downregulate CD4 expression [23].
Viral modulation of NK cell activity Cells that are negative for MHC class I are classic targets of NK cells; therefore, virally-infected cells with reduced MHC class I surface expression are inherently susceptible to attack from NK cells; however, there is evidence that HCMV may have evolved a strategy to protect infected cells that have little or no surface class I from lysis by NK cells. Studies utilizing HCMV-infected endothelial cells that lack surface MHC class I have shown that such cells demonstrate a marked resistance to lysis by allogeneic NK cells [24•]. The HCMV UL18 and the MCMV m144 genes encode an MHC class I homolog that binds β2-microglobulin and is expressed on the cell surface [25,26]. Studies have suggested that these molecules engage inhibitory MHC class I receptors on NK cells, thus protecting infected cells from NK lysis [27]; however, experiments with UL18-knockout virus and with cell lines transfected with the UL18 gene have demonstrated enhanced NK cell killing of UL18+ targets [28••]. Recent findings also indicate that UL18 binds to a novel immunoglobulin superfamily glycoprotein — leukocyte immunoglobulin-like receptor 1 (LIR-1), an inhibitory receptor expressed on monocytes and B cells but on only a minor subset of NK cells [29••]. It has been suggested that UL18 on HCMV-infected cells interacts with LIR-1 on monocytes and suppresses IL-12 production, thereby limiting IL-12-mediated IFN-γ secretion by NK cells [29••]. Analysis of laboratory-propagated HCMV strains and clinical isolates, all of which cause a marked decrease in MHC class I expression, reveals a differential pattern of sensitivity to lysis by NK cells. It appears that cytotoxicity
correlates best with increased surface expression of the adhesion molecule LFA-3 (lymphocyte function-associated antigen 3); the cytotoxicity may result from LFA-3 interaction with CD2 molecules on NK cells [30•]. In summary, subsets of virally infected cells may be able to escape lysis that is mediated by NK cells; however, the molecules and mechanisms responsible for this phenomenon remain controversial and elusive.
Viral inhibition of MHC class II antigen presentation The MHC class II system presents peptides generated in the endosomal–lysosomal system [31]. MHC class II molecules consist of a heterodimer of transmembrane glycoprotein subunits, α and β. In the ER, three MHC class II α and β dimers combine with a homotrimeric invariant chain (termed Ii) forming a nonameric complex [31]. The complex of class II and Ii chains trafficks through the Golgi apparatus, where targeting signals in the cytoplasmic domain of Ii direct the complex to endosomal–lysosomal compartments [31]. In these compartments, proteolysis of the Ii chain produces the class-II-associated Ii-chain peptide (CLIP); this may bind to released class II dimers [31]. Complexes of class I and CLIP traffic to a specialized lysosome-like compartment (the MHC class II compartment) where HLA-DM facilitates the displacement of CLIP molecules with lysosomal peptides in the peptide-binding groove of class II molecules. Peptide-loaded MHC class II molecules move to the cell surface where they present antigen to CD4+ T lymphocytes. CD4+ T lymphocytes are important in controlling viral infections [32]. They secrete cytokines that augment CD8+ T lymphocyte and B lymphocyte responses and that directly inhibit viral replication [33]; moreover, subsets of CD4+ T lymphocytes are capable of lysing virally infected cells in a class-II-restricted fashion [34]. One target of viruses in thwarting antigen presentation by MHC class II may be the trafficking of MHC class II molecules (Figure 1). Studies in HCMV-infected monocyte-derived macrophages demonstrate reduced surface expression of MHC class II, which may result from impaired class II trafficking [35]. A candidate bovine papillomavirus molecule for inhibiting class II trafficking is the E6 protein, which binds to the AP-1 complex that is specific for the trans-Golgi network; this complex is necessary for vesicular trafficking [36•]. MHC class II is constitutively expressed on professional antigen-presenting cells, such as monocytes and B cells, but is upregulated in response to cytokines such as IFN-γ on many other cell types [37]. Recently, experiments have shown that HCMV blocks IFN-γ-stimulated MHC class II expression in human fibroblasts and endothelial cells [38]. The block in IFN-γ-stimulated MHC class II
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Table 1 Effects of viruses on antigen presentation. Effect
Virus
Gene name/product
Mechanism
Adenovirus HCMV MCMV EBV
E1A ? ? BCRF1
Blocks JAK/STAT signal transduction Blocks JAK/STAT signal transduction Inhibits IFN-γ-stimulated MHC class II expression Viral IL-10 homologue; decreases TAP1 expression
HCMV EBV
pp65 EBNA-1
Prevents processing of IE proteins Gly—Ala repeat domain blocks proteasomemediated processing
HSV HCMV
ICP47 US6
Adenovirus HCMV MCMV HCMV
E3-19K US3 m152 US2, US11
HIV
Nef
HIV HCMV BPV
Vpu ? E6
HCMV
UL18
MCMV
m144
Cytokine modulation of antigen presentation
Inhibition of antigen processing
Inhibition of TAP Blocks TAP activity by binding to cytosolic surface of TAP Transmembrane glycoprotein inhibits TAP from within ER lumen
Decrease of MHC trafficking and expression Retains MHC class I molecules in ER Retains MHC class I molecules in ER Retains MHC class I molecules in ER Reverse movement of class I heavy chain from ER to cytoplasm for degradation Accumulation of endocytosed MHC class I molecules in the trans-Golgi, colocalizes with AP-1 complex Degrades MHC class I? Decreases MHC class II in monocytes? Binds AP-1, possibly inhibits trafficking of MHC class II molecules
Expression of viral immunomodulatory molecules Enhances cytolysis by NK cells? Interacts with LIR-1 to inhibit monocyte and B cell activation? Effects on NK cells or monocytes?
BPV, bovine papillomavirus.
expression occurs at the level of IFN-γ-stimulated JAK/STAT (Janus kinase/signal transducer and activator of transcription) signal transduction [39•]. In MCMV-infected bone marrow macrophages, IFN-γstimulated MHC class II expression is also inhibited but by a mechanism not involving IFN-γ-stimulated signal transduction [40•]. The HCMV and MCMV gene products mediating these effects remain to be identified.
Viral inhibition of cytokine-mediated upregulation of MHC antigen presentation Cytokines, particularly the type I and II IFNs, are potent stimulators of antigen processing and MHC expression. IFNs upregulate the transcription of MHC molecules and associated antigen-processing proteins such as the Ii chain, HLA-DM, TAP and proteasome subunits [37,41]. It is as a result of transcriptional control that expression of MHC class I and class II molecules varies between tissues in vivo [42–45]. Several viruses have evolved mechanisms for inhibiting IFN-stimulated MHC expression [46]. Specifically, the adenovirus E1A protein inhibits cellular responses — stimulated by IFN-α and IFN-γ — at the level of JAK/STAT signal
transduction by decreasing STAT1 and p48 expression [47,48]. In an analogous fashion, HCMV inhibits MHC class I and II expression — stimulated by IFN-α and IFN-γ — at the level of JAK/STAT signal transduction by decreasing JAK1 and p48 expression ([39•]; DM Miller, unpublished data). In murine macrophages, MCMV inhibits IFN-γ-stimulated MHC class II expression [40•]. Alternatively, viruses may encode molecules that mimic the action of inhibitory cytokines. EBV encodes an IL-10 homolog which is capable of downregulating TAP1 expression thereby limiting MHC class I antigen presentation [49].
Conclusions Viruses have developed protean means of blocking antigen presentation (Table 1). It is probable that these molecules have arisen from the selective pressures exerted by mammalian immune systems on persistent viruses during their millions of years of coevolution. The resulting viral molecules are highly specific and efficient at blocking multiple levels of antigen processing. In-depth knowledge of their structure and function will lead to a greater understanding of viral persistence and of the
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function of the immune system. These molecules may also prove to be of great value in gene therapy, vaccine design, autoimmunity and transplantation.
14. Sester M, Burgert HG: Conserved cysteine residues within the E3/19K protein of adenovirus type 2 are essential for binding to major histocompatibility complex antigens. J Virol 1994, 68:5423-5432.
Acknowledgements
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The authors are supported by National Institutes of Health grant AI38452-01A1. Daniel Miller was a Howard Hughes Medical Institute Postdoctoral Fellow.
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