Consequences of human cytomegalovirus mimicry

Consequences of Human Cytomegalovirus Mimicry Susan Michelson ABSTRACT: The HCMV genome has evolved with its host by incorporating a series of genes that are homologous to, or functionally mimic, cellular genes. Some are designed to counteract the stress of infection on the host cell, notably the viral antiapoptotic proteins (vICA, vMIA). Others potentially help the infected cell maintain a low immunologic profile. These include virus-encoded chemokine receptors (UL33, UL78, US27, US28), FcRs (gp TRL11/IRL11, gp UL119-118), and proteins that directly or indirectly thwart natural killer cell activity (UL16, gpUL40). In addition, some viral proteins may ABBREVIATIONS aa amino acid CMV cytomegalovirus CREB cyclic AMP response element binding factor FasL Fas ligand FasR Fas receptor FcR receptors for the Fc portion of immunoglobulins gB glycoprotein B GRK GPCR kinase gp glycoprotein GPCR G-protein coupled receptor HCMV human cytomegalovirus IE immediate early Ig immunoglobulin IP3 inositol triphosphate IRL internal repeat long

INTRODUCTION The human cytomegalovirus (HCMV) genome evolved with its host by incorporating genes that functionally mimic cellular genes. Many of these genes appear to be potential modifiers of host immune responses. Their true effects in vivo are hard to ascertain in the complex setting of the whole organism. Nonetheless, their products have the potential to modify proper functioning of cells inFrom the Unite´ d’Immunologie Virale, Institut Pasteur, Paris, France. Address reprint requests to: Dr. Susan Michelson, Unite´ d’Immunologie Virale, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Ce`dex 15, France; Tel: (33) 1 34 62 67 86; Fax: (33) 1 45 68 89 41; E-mail: [email protected]. Received August 12, 2003; revised January 15, 2004; accepted February 3, 2004. Human Immunology 65, 465⫺475 (2004) © American Society for Histocompatibility and Immunogenetics, 2004 Published by Elsevier Inc.

play a role in immunopathology because of fortuitous cross-reactivity with host cell proteins. This overview discusses how these proteins affect the life of the host cell and its immediate neighbors. Human Immunology 65, 465⫺475 (2004). © American Society for Histocompatibility and Immunogenetics, 2004. Published by Elsevier Inc. KEYWORDS: HCMV; mimicry; chemokine receptors; apoptosis

MHC MIC Mr NK PI3K PKC PLC TNF TNFR UL ULBP US TRL vICA vMIA

major histocompatability complex MHC-class I–related molecules relative mobility natural killer phosphatidyl inositol-3-kinase protein kinase C phospholipase C tumor necrosis factor TNF receptor unique long UL16-binding protein unique short terminal repeat long viral inhibitor of caspase-8 apoptosis viral mitochondria-localized inhibitor of apoptosis

volved in immune responses. Viral proteins may interfere with normal cell metabolism, modulate the cell’s immediate environment, and cross-react with host-cell proteins causing autoimmune-like pathologies. How HCMV genes affect the life of the infected cell and its immediate neighbors are the subjects of this review. Functional Manipulation As with all viruses, HCMV’s survival requires survival of its host cell. HCMV has evolved means of combating both death of the host cell and rejection by the host organism. Contact of virus with the cell membrane sets off a series of events that solicit mobilization of both local and global host defense mechanisms. Local events in0198-8859/04/$–see front matter doi:10.1016/j.humimm.2004.02.002

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FIGURE 1 Human cytomegalovirus (HCMV) anti–apoptosis genes. Apoptosis results from ligand (FasL, TNF) binding to death-inducing receptors (Fas, TNFR). Receptor oligomerization follows, the receptors associate with intracellular proteins (FADD, TRADD), leading to recruitment and activation of pro-caspase 8 (FLICE), which in turn activates downstream caspases, and, finally, apoptosis. HCMV anti–apoptotic protein VICA prevents activation of caspase 8. Caspase 8 can activate the protein Bid, which then complexes with apoptotic proteins (Bax or Bak) to induce the release of cytochrome C from mitochondria. Cytochrome C, in a complex with Apaf1, activates caspase 9 followed by activation of caspase 3 and apoptosis. The HCMV VMIA blocks apoptosis upstream of cytochrome C release from mitochondria. For references see discussion of apoptosis in the text.

clude modification of the plasma membrane by insertion of envelope proteins, introduction of virion proteins into the cytoplasm, temporary arrest of cell protein synthesis, chromosome breakage [1], induction of apoptosis (see the following section), and disruption of the cytoskeleton [2] and chromatin organization [3]. All virus-induced events purport to modify cell metabolism to promote latent, persistent, or productive viral replication. A number of HCMV proteins modulate the presentation of major histocompatability complex (MHC) class I and II at the cell surface. Other HCMV proteins interfere with antibody recognition, apoptosis, natural killer (NK) cytotoxicity, and soluble mediator effector mechanisms. These proteins will be examined here from a mechanistic point of view and of how they participate in evading immune detection and destruction at the level of the infected cell.

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The HCMV receptors for the Fc portion of immunoglobulins. The appearance of HCMV receptors for the Fc portion of immunoglobulins (FcRs) depends on viral RNA and protein, but not DNA, synthesis [4]. HCMV FcRs localize within the virion tegument [5]. They are encoded by the virus and are composed of two glycoproteins, gp68 (UL119-118) and gp34 (TRL11/IRL11) [6, 7], that share no homology with classic FcR␥ RI, RII, or RIII, or with any other known protein [8]. They bind with high affinity (Ka ⫽ 2 ⫻ 10⫺8M) and are present at 2 ⫻ 106FcR/infected fibroblast [9]. They have little, if any, affinity for mouse immunoglobulin (Ig)G, but do bind rabbit, pig, horse, cat, and hamster immunoglobulins [9]. HCMV FcRs bind human IgG isotypes with varying affinity (IgG1⬎IgG4⬎IgG2⬎IgG3) [10] and do not bind IgA, IgD, or IgM [9]. Interestingly, ⬎96% of CMV-reactive IgG is present in the IgG1 fraction. Fixation of CMV-specific antibodies to infected cells and virions via their FcR could protect against antibodydependent cell cytotoxicity; literature on HCMV is strikingly devoid of articles on HCMV antibody-dependent cell cytotoxicity. Viral FcRs could play a role in the dissemination of antibody-complexed viruses [11] and perhaps antibody-coated bacteria. Antiviral FcR idiotypic antibodies might also masquerade as rheumatoid factors [12]. Apoptosis. Apoptosis serves to rid the organism of cells with irreparable injuries (reviewed in [13]). The need for

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HCMV to have evolved anti–apoptotic proteins is evident: infection not only arrests the cell cycle (reviewed by [14]), but stresses the cell in general. Enhanced apoptosis occurs after mere contact of hematopoietic precursors with dense bodies and virions [15]. It is also initiated by interaction of a ligand (tumor necrosis factor [TNF]-␣ or FasL) with death-inducing cell surface receptors (TNF receptor [TNFR] or Fas) (Figure 1). HCMV upregulates Fas and TNFR on infected fibroblasts [16, 17]. Apoptosis may also be mediated by attachment of cytotoxic lymphocytes to infected targets with subsequent release of perforin and granzyme. HCMV infection of dendritic cells may lead to blunting of immune responses because it induces apoptosis by upregulating FasL and TRAIL on infected dendritic cells [18]. Immediate early (IE)72 expression induces accumulation of p53 [19] that could lead to apoptosis were it not for p53-IE86 interactions; the N-terminal domain of IE86 binds to the repressor domain of p53, inhibiting its activity [20, 21]. IE protein expression protects smooth muscle [22] and endothelial cells [23, 24] from HCMVinduced apoptosis. Some other unknown HCMV protein(s) block the p53 nuclear NLS [25], sequestering p53 in the cytoplasm [26]. The HCMV US21 open reading frame may encode another anti–apoptotic protein [27]. US21 is homologous to the human lifeguard protein, which potentially protects against Fas-mediated apoptosis [28]. HCMV encodes two additional anti–apoptotic proteins, viral mitochondria-localized inhibitor of apoptosis (vMIA) [29, 30] and viral inhibitor of caspase-8 apoptosis (vICA) [31]. vMIA, a functional analogue of bcl2, is encoded by exon 1 of UL37 of HCMV and appears at IE times after infection. Full-length gpUL37, which has additional transmembrane and cytoplasmic domains, also confers protection from apoptosis [32]. Both UL37-derived proteins transit through the Golgi before reaching their final destination in mitochondria [32]. vMIA carries two domains (aa 5 to 34 and 118 to 147), the first being responsible for its predominantly mitochondrial localization [30]. vMIA inhibits apoptosis mediated by FasL, cytotoxic drugs, and infection with an adenovirus E1B19K-deletion mutant [33]. It blocks apoptosis at a point downstream of caspase 8 activation, but upstream of cytochrome C release from mitochondria (see Figure 1). vMIA complexes with an adenine nucleotide translocation, a component of the mitochondrial transition pore complex [33]. VMIA protein is essential for viral replication [29], which explains its high level of sequence conservation among clinical isolates of HCMV [30], with variations occurring outside the domain implicated in its anti–apoptotic function. vICA, a functional analogue of FLIP, is encoded by an immediate early gene, UL36 [31]. vICA inhibits proteo-

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lytic activation of pro-caspase 8. In contrast to vMIA, vICA is not essential for viral replication. Neither protein shows homology to its functional homologue. Interference with NK cytotoxicity. NK cells represent the first innate line of defense against CMV infections (reviewed by [34]). NK cells bear receptors that mediate either activating or inhibitory signals. A balanced stimulation of these receptors determines the fate of cells targeted by the NK cell. NKG2D, an activating receptor, interacts with a variety of normal cellular ligands: ULBPs, 1, 2, and 3, and MHC-class I–related molecules (MICs) A and B (reviewed in [35]). Involvement of NKG2D in NK cell–mediated cytotoxicity correlates with expression and surface density of its ligands on target cells [36]. NKG2D is also found on activated CD8⫹ lymphocytes. The name “ULBP” is based on the fact that these cellular proteins bind the HCMV protein encoded by UL16 [37], a 50kD early, nonessential glycoprotein [38]. ULBP signal transduction occurs via PI3K, Janus kinase 2, and STAT 5, leading to activation of externally regulated kinase/mitogen-activated protein kinase [39]. HCMV infection induces all know ligands of NKG2D in the infected cell [40, 41], but UL16 selectively sequesters MIC B and ULBPs 1 and 2 in the cytoplasm [41, 42]. In B cells stably transfected with UL16, MIC B fails to transit the Golgi, a block mediated by a tyrosine-based motif in the cytoplasmic tail of UL16 [43]. Addition of soluble pUL16 competitively inhibits NKG2D activation by ULBPs [44]. Cells infected with wild-type HCMV showed significant resistance to cytotoxic proteins [45], whereas infection with UL16-deletion mutants increased susceptibility to NK lysis as much as 70% [41, 45, 46]. HCMV also inhibits NK cell activity indirectly via the inhibitory receptor CD94 (NKG2A) that interacts with human leukocyte antigen (HLA)-E molecules on the surface of cells. HLA-E surface expression depends on attachment of a nonapeptide (VMAPRTLIL), cleaved from the N-terminal of HLA-A, B, and C molecules, and ensures HLA-E trans-Golgi transportation. To combat possible downregulation of HLA-E by HCMV, the virus encodes an early glycoprotein (gpUL40) bearing a nonapeptide identical to that of HLA-C. This UL40-derived nonapeptide is delivered directly into the ergastoplasm, thus bypassing the need for TAPs, the activity of which is also inhibited by the HCMV US6 gene product [47, 48]. Cleavage of UL40 thus affords presentation of HLA-E on infected cells, despite depletion of cellular MHC-I molecules [49, 50]. The potential role of gpUL40 to protect cells from NK lysis by facilitating HLA-E remains open for discussion [51–53].

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Chemokines and Chemokine Receptors Lymphocyte trafficking and effector mechanisms depend on chemokines (review [54]), which attract cells involved in innate and adaptive immunity to sites of infection and play a role in the ultimate activation of their effector mechanisms [55, 56]. All chemokines have the same basic structure. Although one chemokine may bind to several receptors and vice versa, these interactions occur only within a given subfamily with no inter-subfamily promiscuity. Sequencing of the AD169 strain of CMV in 1990 [57] revealed three genes with homology to G-protein coupled receptors (GPCRs): UL33, US27, and US28 [58]. A fourth GPCR-like protein, UL78, was found by homology with a human herpesvirus-6 gene [59]. Phylogenetically, US27, US28, and UL78 appear to cluster with mouse, rat, and human CX3CRs [60]. UL33 is in a cluster with CXCR4; it would therefore be interesting to see if UL33 binds SDF-1, the unique ligand of CXCR4. Cloning of cellular GPCRs revealed their homology to the HCMV US28 gene (reviewed in [60]). UL27, US28 [61], UL33 [62, 63], and UL78 [64] deletion mutants are dispensable for viral replication in vitro. No one has yet deleted all four genes simultaneously from HCMV to assess their collective role in viral replication. pUS28 binds a variety of CC (CCL2, 3, 4, 5, and 7), but not CXC, chemokines with affinities in the order of 10⫺9 to 10⫺10 M, leading to calcium mobilization [61, 65, 66]. Kledal et al. [67] showed that pUS28 bound even more avidly CX3CL1, which exists in both a soluble and a membrane-bound form. pUS28 expression reduced extracellular accumulation of constitutively expressed CCL2 [61] and CCL5 [61, 68] induced by infection of fibroblasts. CCL2 and CCL7 were reduced in supernatant of HCMV-infected retinal pigment epithelial cells [69] and CCL5 from infected endothelial cell supernatant [70]. Infection with US28- [61, 68] or with US27 ⫹ US28 deletion mutants [61] failed to downregulate extracellular CCL5 or CCL2 accumulation. CCL5 is continuously internalized into cells infected with mutants deleted of either US28 or US27, but not with the double mutant [61]. Expression of US28 enhances cell-to-cell fusion [71] and promotes migration of smooth muscle cells [72]. US28-transfected cells bind firmly to immobilized CX3CL1 under flow conditions in the absence of integrins [73], suggesting that US28 might facilitate transendothelial migration and viral dissemination by latently infected monocytes in vivo (see model in [60]). US28 mRNA is found in vivo in peripheral blood monocytes [74] and is expressed at immediate early times [75] in latently HCMV-infected monocytic cells in vitro [76]. pUS28 can act as a coreceptor for human immunodefi-

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ciency virus [78, 79]. These properties of pUS28 might contribute to HCMV’s role in the rapid aggravation of acquired immunodeficiency syndrome in congenitally coinfected children [77]. Recently, advances on pUS28 endocytosis and pUS28 and pUL33 signaling (Figure 2) have been reported. US28 endocytosis and signaling are separable phenomena. US28 is internalized continuously and enters endosomal and lysosomal compartments, where the majority (⯝80%) is found [80, 81], then recycles to the surface. US28 endocytosis depends on its C-terminal domain because deletion or exchange with that of a cellular (NK1) or viral (ORF 74) receptor blocks endocytosis [82]. A palmitoylation site within the C-terminus appears important, as was shown for the cellular CCR5 [83]. US28 endocytosis also depends on clathrin, but not on ␤-arrestin mobilization [80, 81]. Although US28 does not internalize in response to CCL5, prolonged treatment with CX3CL1 leads to considerable loss of US28 membrane expression [80]. In contrast to US28 endocytosis, constitutive signaling by US28 occurs independently of the C-terminus and of receptor endocytosis [82, 84]. Deletion or swapping of the C-terminus of US28 actually enhanced its constitutive activity [82, 84]. US28 and UL33 can couple to Pertussis toxin–sensitive G␣ proteins [85, 86], but associate predominantly with PTX insensitive G␣q/11 proteins in both transfected [72, 84, 86] and infected cells [86, 87]. Both receptors constitutively activate phospholipase C (PLC) [63, 88]. US28 activates PLC via G␤/␥ subunit [89]. PLC activation by both US28 and UL33 leads to accumulation of inositol triphosphate (IP3), phosphorylation of p38 MAK and activation of CRE-mediated transcription [63, 84, 86, 88]. UL33 activation of CRE-dependent transcription is mediated by Rho proteins [86]. Only US28 activates NF␬B. US28 is naturally hyperphosphorylated in cells in the absence of ligand [84, 90]. Phosphorylation leads to mobilization of ␤-arrestins to the receptor with subsequent attenuation of signaling. US28 phosphorylation increased on overexpression of GPCR kinase (GRK) 2 [84, 90], and, to a lesser extent, of GRK 5 [84]. Coexpression of an active form of GRK2 inhibited IP3 stimulation by UL33 [86]. GRK2 contains an RGS-like domain that binds to G␣q proteins, such that even the kinase-inactive form of GRK2 still attenuated US28 stimulation of IP3 formation [84], probably via sequestration of G␣q subunits. Potential phosphorylation sites within the pUS28 Cterminus were studied using specific inhibitors of various kinases and point mutations [90]. Inhibition of casein kinase-2 had the greatest effect on US28 phosphorylation. Inhibition of PKC reduced it, but stimulation of PKC did not elicit an evident increase. Phosphopeptide

Human Cytomegalovirus Molecular Mimicry

FIGURE 2 Human cytomegalovirus (HCMV) G-protein coupled receptor signaling HCMV UL33 and UL28 receptors couple to both G␣i/o and G␣q/11 proteins. Signaling leads to activation of phospholipase C (PLC) 3 IP3 accumulation, and 3 p38 mitogen-activated protein kinase K and activation of CRE-dependent transcription. Only US28 is activate NF␬B. US28 endocytosis in dependent on the C-terminus (lightening). This domain is regulated by phosphorylation by a number of different kinases (GPCR kinases 2 and 5, protein kinase C and casein kinase-2 ). Substantial phosphorylation occurs on 10/12 C-terminal serines (S) indicated by (*) with serines indicated by (**) being more prominent targets for phosphorylation. Threonines are phosphorylated to a lesser degree. Constitutive US28 activity is not affected by deletion of the C-terminus (US28⌬carboxyl terminus). References are given in the text.

profiles showed that C-terminal serines are more phosphorylated than threonines. No tyrosine residues were phosphorylated. Substitutions of serines and threonines with alanine demonstrated that mutation of some serines (338, 339, 343) reduced US28 phosphorylation more than others (323, 325, 327, 330, 331, and 333); serines 315 and 319 did not contribute [90]. Mutation of all serines and threonines led to enhanced US28 membrane expression, but reduced CCL5 internalization (see Figure 2). Finally, US28 constitutive activity (G␣q/11 coupling, IP3 stimulation) is independent of the N-terminal 22 aa of US28 [91]. Combined study of point mutations

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and a recently described nonpeptidergic inhibitor of US28 constitutive activity [91] should help define regions of US28 crucially involved in its activity. Dimerization of chemokine receptors can be important for GPCR signaling (reviewed in [92]) and crosstalk between cellular and viral GPCRs could have synergistic effects on signaling ([93] and review by [94]). The multiplicity of GPCR sequences [95] and their conservation in the primate CMV genomes [96 –98] suggests they must be important in the viral life cycle in vivo. Constitutive activity of US28 and UL33 elicits activation of promoters via cyclic AMP response element binding factor (CREB)-responsive elements [63, 82, 86]. US28 expression also leads NF␬B activation [88], response elements that play an important role in major immediate early promoter– driven transcription [99, 100]. UL33 is present on the surface of virions [101], as is US28 of rhesus CMV [98]. If these signal-transducing receptors are effectively integrated into cell membranes on viral entry, they may participate in host-cell activation of viral genome expression. Antigenic cross-reactivity. Viral mimicry may inadvertently participate in immunopathology (reviewed in [102]). Virus can elicit adverse cross-reactivities in two ways: (1) exposure of intracellular proteins not recognized as part of the self-repertoire on viral cell lysis and

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T cells from patients suffering from the autoimmune stiff-man syndrome target glutamic acid decarboxylase 65 [109]. Despite homology of this HCMV DNA-binding protein with that of other herpesviruses, the sequence of the peptide recognized in the HCMV protein (aa 674-687) differs substantially from that of other herpesviruses. There is increasing evidence of T-cell repertoire degeneracy (reviewed in [110]). On successive infections, epitopes shared by different pathogens can divert and amplify the immune response to a given epitope induced by another, unrelated microbe (reviewed in [111]) affecting both protective immunity and immunopathology [112]. Although a CMV protein(s) is unlikely to cause an autoimmune disease, cross-reactive antibodies might exacerbate an existing condition, as suggested by clinical studies [113].

FIGURE 3 Antigenic mimicry between human cytomegalovirus (HCMV) UL94 and an endothelial cell integrin. Antibodies against HCMV UL94 recognize the same immunodominant peptide as antibodies in serum from patients suffering from systemic sclerosis. Both antibodies recognize a peptide within an endothelial cell integrin NAG-2 and can induce apoptosis in endothelial cells [108]. Identity (*) and similarity ( : ) of these peptides is indicated.

(2) fortuitous identity between viral and host protein epitopes. Autoimmune manifestations occur during CMV disease [103]. Recently, the appearance of anti– endothelial, anti–smooth muscle cell, and anti–nuclear antibodies in liver transplant recipients correlated with development of CMV disease [104]. Soderberg et al. suggested that anti-CD13 autoantibodies found in CMV-infected bone marrow transplant recipients [105, 106], may be associated with graft-versus-host disease. A strong correlation between CMV infection and development of anti– endothelial cell antibodies occurs in renal and cardiac graft recipients [107]. Antibodies specific for a systemic sclerosis (SSc) peptide recognize a late 36kD HCMV protein conserved among herpesviruses [108] (Figure 3). Affinity purified antibodies against the immunodominant SSc peptide recognize pUL94 and a NAG-2 integrin epitope on the surface of endothelial cells. Binding of either anti-SSc or anti-UL94 antibodies to endothelial cells caused apoptosis. There is a 1 in 3.2 ⫻ 106– 4.096 ⫻ 1015 chance that a linear sequence of 5 to 12 aa would be identical in a viral and a host protein. CMV proteins also elicit activation of non-CMV specific CD4 T cells. An HLA-DR3–restricted, anti– glutamic acid decarboxylase 65–specific CD4 clone recognized the HCMV DNA-binding protein, pUL57. CD4⫹

Immune evasion and mimicry. The known functions of many HCMV-encoded proteins seem principally devoted to immune evasion. Through its capacity to induce cellto-cell fusion [71] and firmly attach cells to immobilized CX3CL1 [73], US28 could also play a role in viral dissemination shielded from humoral immunity. US28 sequestration of chemokines affords removal of soluble mediators important for lymphocyte attraction and activation. HCMV-encoded antiapoptotic proteins protect infected cells from cytotoxic lymphocytes. UL16 encodes a decoy protein capable of countering stimulation of an NK cell activation receptor. pUL18 plays some role in protection from lysis by a LIR-1-positive subset of NK cells [114, 115]. CMV FcRs may render anti-CMV antibodies ineffective. HCMV appears to carry many genes whose demonstrated or potential functions aim to allow the virus to reside in harmony with its host. It remains very difficult to assess the true in vivo functions of HCMV genes that potentially interact with the immune system. Such assessment will require much careful clinical study and should be greatly assisted by studying existing animal models. ACKNOWLEDGMENTS

Many thanks to Dr. Bahram Bodaghi for their critical reading of the manuscript and to Dr. Olivier Pleskoff for his counsel. We are very grateful to Dr. Cathrien Bruggeman and her group for their gift of the abstract book of the CMV and Betaherpesvirus workshops.

REFERENCES 1. Fortunato EA, Dell’Aquila ML, Spector DH: Specific chromosome 1 breaks induced by human cytomegalovirus. Proc Natl Acad Sci U S A 97:853, 2000.

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2. Jones NL, Kilpatrick BA: The effects of human cytomegalovirus infection on cytoskeleton-associated polysomes. Eur J Cell Biol 46:31, 1988. 3. Kamata T, Tanaka S, Watanabe Y: Human cytomegalovirus-induced chromatin factors responsible for changes in template activity and structure of infected cell chromatin. Virology 90:197, 1978. 4. Gonczol E, Boldogh I, Vaczi L: IgG-Fc-binding receptors in cells abortively infected, or transformed, by human cytomegalovirus. Acta Microbiol Acad Sci Hung 28:157, 1981. 5. Stannard LM, Hardie DR: An Fc receptor for human immunoglobulin G is located within the tegument of human cytomegalovirus. J Virol 65:3411, 1991. 6. Lilley BN, Ploegh HL, Tirabassi RS: Human cytomegalovirus open reading frame TRL11/IRL11 encodes an immunoglobulin G Fc-binding protein. J Virol 75:11218, 2001. 7. Atalay R, Zimmermann A, Wagner M, Borst E, Benz C, Messerle M, Hengel H: Identification and expression of human cytomegalovirus transcription units coding for two distinct Fc-gamma receptor homologs. J Virol 76: 8596, 2002. 8. Maccormac LP, Grundy JE: Human cytomegalovirus induces an Fc gamma receptor (Fc(Gamma)R) in endothelial cells and fibroblasts that is distinct from the human cellular Fc(Gamma)Rs. J Infect Dis 174:1151, 1996. 9. Antonsson A, Johansson PJ: Binding of human and animal immunoglobulins to the IgG Fc by human cytomegalovirus. J Gen Virol 82:1137, 2001. 10. Murayama T, Natsuume-Sakai S, Shimokawa K, Furukawa T: Fc receptor(s) induced by human cytomegalovirus bind differentially with human immunoglobulin G subclasses. J Gen Virol 67:1475, 1986. 11. McKeating JA, Griffiths PD, Weiss RA: HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor. Nature 343:659, 1990. 12. Tsuchiya N, Murayama T, Yoshinoya S, Matsuta K, Shiota M, Furukawa T, Ito K: Antibodies to human cytomegalovirus 65-kilodalton Fc binding protein in rheumatoid arthritis: idiotypic mimicry hypothesis of rheumatoid factor production. Autoimmunity 15:39, 1993. 13. Zimmerman K, Bonzon C, Green D: The machinery of programmed cell death. Pharm Therap 92:57, 2001. 14. Fortunato EA, McElroy AK, Sanchez I, Spector DH: Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus. Trends Microbiol 8:111, 2000. 15. Sindre H, Rollag H, Olafsen MK, Degre M, Hestdal K: Human cytomegalovirus induces apoptosis in the hematopoietic cell line MO7e. APMIS 108:223, 2000. 16. Chaudhuri AR, St Jeor S, Maciejewski JP: Apoptosis induced by human cytomegalovirus infection can be

471

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

enhanced by cytokines to limit the spread of virus. Exp Hematol 27:1194, 1999. Arrode G, Boccaccio C, Lule J, Allart S, Moinard N, Abastado JP, Alam A, Davrinche C: Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infected fibroblasts is cross-presented to CD8(⫹) T cells by dendritic cells. J Virol 74:10018, 2000. Raftery MJ, Schwab M, Eibert SM, Samstag Y, Walczak H, Schonrich G: Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 15:997, 2001. Castillo JP, Yurochko AD, Kowalik TF: Role of human cytomegalovirus immediate-early proteins in cell growth control. J Virol 74:8028, 2000. Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE: Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265: 391, 1994. Tsai HL, Kou GH, Chen SC, Wu CW, Lin YS: Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. J Biol Chem 271:3534, 1996. Tanaka K, Zou JP, Takeda K, Ferrans VJ, Sandford GR, Johnson TM, Finkel T, Epstein SE: Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells. Circulation 99:1656, 1999. Cinatl Jr. J, Cinatl J, Vogel JU, Rabenau H, Kornhuber B, Doerr HW: Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells. Intervirology 39:259, 1996. Wang J, Marker PH, Belcher JD, Wilcken DE, Burns LJ, Vercellotti GM, Wang XL: Human cytomegalovirus immediate early proteins upregulate endothelial p53 function. FEBS Lett 474:213, 2000. Wang J, Belcher JD, Marker PH, Wilcken DE, Vercellotti GM, Wang XL: Cytomegalovirus inhibits p53 nuclear localization signal function. J Mol Med 78:642, 2001. Kovacs A, Weber ML, Burns LJ, Jacob HS, Vercellotti GM: Cytoplasmic sequestration of p53 in cytomegalovirus-infected human endothelial cells. Am J Pathol 149:1531, 1996. Holzerlandt R, Orengo C, Kellam P, Alba MM: Identification of new herpesvirus gene homologs in the human genome. Genome Res 12:1739, 2002. Somia N, Schmitt M, Vetter D, van Antwerp D, Heinemann S, Verma I: LFG: an anti-apoptotic gene that provides protection from Fas-mediated cell death. Proc Natl Acad Sci U S A 96:12667, 1999. Goldmacher VS, Bartle LM, Skaletskaya A, Dionne CA, Kedersha NL, Vater CA, Han JW, Lutz RJ, Watanabe S, Cahir McFarland ED, Kieff ED, Mocarski ES, Chittenden T: A cytomegalovirus-encoded mitochondria-lo-

472

30.

31.

32.

33. 34.

35.

36.

37.

38.

39.

40.

41.

S. Michelson

calized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sci U S A 96:12536, 1999. Hayajneh WA, Colberg-Poley AM, Skaletskaya A, Bartle LM, Lesperance MM, Contopoulos-Ioannidis DG, Kedersha NL, Goldmacher VS: The sequence and antiapoptotic functional domains of the human cytomegalovirus UL37 exon 1 immediate early protein are conserved in multiple primary strains. Virology 279:233, 2001. Skaletskaya A, Bartle LM, Chittenden T, McCormick AL, Mocarski ES, Goldmacher VS: A cytomegalovirusencoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc Natl Acad Sci U S A 98:7829, 2001. Colberg-Poley AM, Patel MB, Erezo DP, Slater JE: Human cytomegalovirus UL37 immediate-early regulatory proteins traffic through the secretory apparatus and to mitochondria. J Gen Virol 81:1779, 2000. Goldmacher VS: vMIA, a viral inhibitor of apoptosis targeting mitochondria. Biochimie 84:177, 2002. Farrell HE, Degli-Esposti MA, Davis-Poynter NJ: Cytomegalovirus evasion of natural killer cell responses. Immunol Rev 168:187, 1999. Diefenbach A, Raulet DH: The innate immune response to tumors and its role in the induction of T-cell immunity. Immunol Rev 188:9, 2002. Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A: Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62:6178, 2002. Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ: ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14:123, 2001. Kaye J, Browne H, Stoffel M, Minson T: The UL16 gene of human cytomegalovirus encodes a glycoprotein that is dispensable for growth in vitro. J Virol 66:6609, 1992. Sutherland CL, Chalupny NJ, Schooley K, VandenBos T, Kubin M, Cosman D: UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J Immunol 168:671, 2002. Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, Rammensee HG, Steinle A: Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein. Eur J Immunol 33:194, 2003. Rolle A, Mousavi-Jazi M, Eriksson M, Odeberg J, Soderberg-Naucler C, Cosman D, Karre K, Cerboni C: Effects of human cytomegalovirus infection on ligands for the activating NKG2D receptor of NK cells: up-regulation of UL16-binding protein (ULBP)1 and ULBP2 is coun-

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

teracted by the viral UL16 protein. J Immunol 171:902, 2003. Dunn C, Chalupny NJ, Sutherland CL, Dosch S, Sivakumar PV, Johnson DC, Cosman D: Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. J Exp Med 197:1427, 2003. Wu J, Chalupny NJ, Manley TJ, Riddell SR, Cosman D, Spies T: Intracellular retention of the MHC class I-related chain B ligand of NKG2D by the human cytomegalovirus UL16 glycoprotein. J Immunol 170:4196, 2003. Kubin M, Cassiano L, Chalupny J, Chin W, Cosman D, Fanslow W, Mullberg J, Rousseau AM, Ulrich D, Armitage R: ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. Eur J Immunol 31: 1428, 2001. Odeberg J, Browne H, Metkar S, Froelich CJ, Branden L, Cosman D, Soderberg-Naucler C: The human cytomegalovirus protein UL16 mediates increased resistance to natural killer cell cytotoxicity through resistance to cytolytic proteins. J Virol 77:4539, 2003. Vales-Gomez M, Browne H, Reyburn HT: Expression of the UL16 glycoprotein of Human Cytomegalovirus protects the virus-infected cell from attack by natural killer cells. BMC Immunol 4:4, 2003. Lehner PJ, Karttunen JT, Wilkinson GWG, Cresswell P: The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sci U S A 94:6904, 1997. Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz E, Ploegh HL, Peterson PA, Yang Y, Fruh K: The ERluminal domain of the HCMV glycoprotein US6 inhibits peptide translocation By TAP. Immunity 6:613, 1997. Tomasec P, Braud VM, Rickards C, Powell MB, McSharry BP, Gadola S, Cerundolo V, Borysiewicz LK, McMichael AJ, Wilkinson GW: Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287:1031, 2000. Cerboni C, Mousavi-Jazi M, Wakiguchi H, Carbone E, Karre K, Soderstrom K: Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLAE-dependent protection from NK cell-mediated cytotoxicity. Eur J Immunol 31:2926, 2001. Falk CS, Mach M, Schendel DJ, Weiss EH, Hilgert I, Hahn G: NK cell activity during human cytomegalovirus infection is dominated by US2-11-mediated HLA class I down-regulation. J Immunol 169:3257, 2002. Ulbrecht M, Martinozzi S, Grzeschik M, Hengel H, Ellwart JW, Pla M, Weiss EH: Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand

Human Cytomegalovirus Molecular Mimicry

53.

54. 55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

for HLA-E and prevents NK cell-mediated lysis. J Immunol 164:5019, 2000. Wang EC, McSharry B, Retiere C, Tomasec P, Williams S, Borysiewicz LK, Braud VM, Wilkinson GW: UL40mediated NK evasion during productive infection with human cytomegalovirus. Proc Natl Acad Sci U S A 99:7570, 2002. Baggiolini M: Chemokines in pathology and medicine. J Intern Med 250:91, 2001. Taub DD, Ortaldo JR, Turcovski-Corrales SM, Key ML, Longo DL, Murphy WJ: Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production. J Leukoc Biol 59:81, 1996. Taub DD, Sayers TJ, Carter CR, Ortaldo JR: Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. J Immunol 155:3877, 1995. Chee MS, Bankier AT, Beck S, Bohni R, Brown CM, Cerny R, Horsnell T, Hutchison CAD, Kouzarides T, Martignetti JA, et al: Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Topics Microbiol Immunol 154:125, 1990. Chee MS, Satchwell SC, Preddie E, Weston KM, Barrell BG: Human cytomegalovirus encodes three G proteincoupled receptor homologues. Nature 344:774, 1990. Gompels UA, Nicholas J, Lawrence G, Jones M, Thomson BJ, Martin ME, Efstathiou S, Craxton M, Macaulay HA: The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 209:29, 1995. Beisser P, Goh C-S, Cohen F, Michelson S: Viral chemokine receptors and chemokines in human cytomegalovirus trafficking and interaction with the immune system. In:Koszinowski U, Hengel H (eds): Viral Proteins Counteracting Host Defenses, vol 269. Berlin: Springer-Verlag, 2002. Bodaghi B, Jones TR, Zipeto D, Vita C, Sun L, Laurent L, Arenzana-Seisdedos F, Virelizier JL, Michelson S: Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: Withdrawal of chemokines from the environment of cytomegalovirus-infected cells. J Exp Med 188:855, 1998. Margulies BJ, Browne H, Gibson W: Identification of the human cytomegalovirus G protein-coupled receptor homologue encoded by UL33 in infected cells and enveloped virus particles. Virology 225:111, 1996. Casarosa P, Bakker RA, Verzijl D, Navis M, Timmerman H, Leurs R, Smit MJ: Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J Biol Chem 276:1133, 2001. Detlef M, Milotic I, Vaida B, Mertens T: The human cytomegalovirus U78 gene: transcription and role for replication in fibroblasts and ex-vivo human renal arteries. 9th International Cytomegalovirus Workshop and

473

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

1st International Betaherpesvirus Workshop. Maastricht, NL, 2003, Abstract I.08. Gao JL, Murphy PM: Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. J Biol Chem 269:28539, 1994. Kuhn DE, Beall CJ, Kolattukudy PE: The cytomegalovirus US28 protein binds multiple CC chemokines with high affinity. Biochem Biophys Res Commun 211:325, 1995. Kledal TN, Rosenkilde MM, Schwartz TW: Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett 441:209, 1998. Vieira J, Schall TJ, Corey L, Geballe AP: Functional analysis of the human cytomegalovirus US28 gene by insertion mutagenesis with the green fluorescent protein gene. J Virol 72:8158, 1998. Momma Y, Nagineni CN, Chin MS, Srinivasan K, Detrick B, Hooks JJ: Differential expression of chemokines by human retinal pigment epithelial cells infected with cytomegalovirus. Invest Ophthalmol Vis Sci 44:2026, 2003. Billstrom Schroeder M, Worthen GS: Viral regulation of rantes expression during human cytomegalovirus infection of endothelial cells. J Virol 75:3383, 2001. Pleskoff O, Treboute C, Alizon M: The cytomegalovirusencoded chemokine receptor US28 can enhance cell-cell fusion mediated by different viral proteins. J Virol 72: 6389, 1998. Streblow DN, Soderberg-Naucler C, Vieira J, Smith P, Wakabayashi E, Ruchti F, Mattison K, Altschuler Y, Nelson JA: The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99:511, 1999. Haskell CA, Cleary MD, Charo IF: Unique role of the chemokine domain of fractalkine in cell capture. Kinetics of receptor dissociation correlate with cell adhesion. J Biol Chem 275:34183, 2000. Patterson BK, Landay A, Andersson J, Brown C, Behbahani H, Jiyamapa D, Burki Z, Stanislawski D, Czerniewski MA, Garcia P: Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission. Am J Pathol 153:481, 1998. Zipeto D, Bodaghi B, Laurent L, Virelizier JL, Michelson S: Kinetics of transcription of human cytomegalovirus chemokine receptor US28 in different cell types. J Gen Virol 80:543, 1999. Beisser PS, Laurent L, Virelizier JL, Michelson S: Human cytomegalovirus chemokine receptor gene US28 is transcribed in latently infected THP-1 monocytes. J Virol 75:5949, 2001. Kovacs A, Schluchter M, Easley K, Demmler G, Shearer W, La Russa P, Pitt J, Cooper E, Goldfarb J, Hodes D,

474

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

S. Michelson

Kattan M, McIntosh K: Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1infected women. N Engl J Med 341:77, 1999. Rucker J, Edinger AL, Sharron M, Samson M, Lee B, Berson JF, Yi Y, Margulies B, Collman RG, Doranz BJ, Parmentier M, Doms RW: Utilization of chemokine receptors, orphan receptors, and herpesvirus-encoded receptors by diverse human and simian immunodeficiency viruses. J Virol 71:8999, 1997. Pleskoff O, Treboute C, Brelot A, Heveker N, Seman M, Alizon M: Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. Science 276:1874, 1997. Fraile-Ramos A, Kledal TN, Pelchen-Matthews A, Bowers K, Schwartz TW, Marsh M: The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. Mol Biol Cell 12:1737, 2001. Fraile-Ramos A, Kohout TA, Waldhoer M, Marsh M: Endocytosis of the viral chemokine receptor US28 does not require beta-arrestins but is dependent on the clathrin-mediated pathway. Traffic 4:243, 2003. Waldhoer M, Casarosa P, Rosenkilde MM, Smit MJ, Leurs R, Whistler JL, Schwartz TW: The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis. J Biol Chem 278:19473, 2003. Percherancier Y, Planchenault T, Valenzuela-Fernandez A, Virelizier JL, Arenzana-Seisdedos F, Bachelerie F: Palmitoylation-dependent control of degradation, life span, and membrane expression of the CCR5 receptor. J Biol Chem 276:31936, 2001. Miller WE, Houtz DA, Nelson CD, Kolattukudy PE, Lefkowitz RJ: GRK phosphorylation and beta arrestin recruitment regulate the constitutive signaling activity of the human cytomegalovirus US28 GPCR. J Biol Chem 13:21663, 2003. Billstrom MA, Johnson GL, Avdi NJ, Worthen GS: Intracellular signaling by the chemokine receptor US28 during human cytomegalovirus infection. J Virol 72: 5535, 1998. Casarosa P, Gruijthuijsen YK, Michel D, Beisser PS, Holl J, Fitzsimons CP, Verzijl D, Bruggeman CA, Mertens T, Leurs R, Vink C, Smit MJ: Constitutive signaling of the human cytomegalovirus-encoded receptor UL33 differs from that of its rat cytomegalovirus homolog R33 by promiscuous activation of G proteins of the Gq, Gi as well as Gs class. J Biol Chem 12:50010, 2003. Minisini R, Tulone C, Luske A, Michel D, Mertens T, Gierschik P, Moepps B: Constitutive inositol phosphate formation in cytomegalovirus-infected human fibroblasts is due to expression of the chemokine receptor homologue pUS28. J Virol 77:4489, 2003. Waldhoer M, Kledal TN, Farrell H, Schwartz TW:

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. J Virol 76:8161, 2002. Wu D, C-K H, Jiang H: Roles of phospholipid signaling in chemoattractant-induced responses. J Cell Sci 113: 2935, 2000. Mokros T, Rehm A, Droese J, Oppermann M, Lipp M, Hopken UE: Surface expression and endocytosis of the human cytomegalovirus-encoded chemokine receptor US28 is regulated by agonist-independent phosphorylation. J Biol Chem 277:45122, 2002. Casarosa P, Menge WM, Minisini R, Otto C, van Heteren J, Jongejan A, Timmerman H, Moepps B, Kirchhoff F, Mertens T, Smit MJ, Leurs R: Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. J Biol Chem 278:5172, 2003. Mellado M, Vila-Coro A, Martinez C, Rodriguez-Frade J: Receptor dimerization: a key step in chemokine signaling. Cell Mol Biol 47:575, 2001. Bakker RA, Casarosa P, Timmerman H, Smit MJ, Leurs R: Constitutively active Gq/11-coupled receptors enable signalling by co-expressed Gi/o-coupled receptors. J Biol Chem 10:10, 2003. Selbie L, Hill S: G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. Trends Pharmacol Sci 19:87, 1998. Rigoutsos I, Novotny J, Huynh T, Chin-Bow ST, Parida L, Platt D, Coleman D, Shenk T: In silico pattern-based analysis of the human cytomegalovirus genome. J Virol 77:4326, 2003. Hansen SG, Strelow LI, Franchi DC, Anders DG, Wong SW: Complete sequence and genomic analysis of Rhesus cytomegalovirus. J Virol 77:6620, 2003. Martin WJ: Melanoma growth stimulatory activity (MGSA/GRO-alpha) chemokine genes incorporated into an African green monkey simian cytomegalovirus-derived stealth virus. Exp Mol Pathol 66:15, 1999. Penfold ME, Schmidt TL, Dairaghi DJ, Barry PA, Schall TJ: Characterization of the Rhesus cytomegalovirus US28 Locus. J Virol 77:10404, 2003. Stinski MF, Roehr TJ: Activation of the major immediate early gene of human cytomegalovirus by cis-acting elements in the promoter-regulatory sequence and by virus-specific trans-acting components. J Virol 55:431, 1985. Cherrington JM, Mocarski ES: Human cytomegalovirus ie1 transactivates the alpha promoter-enhancer via an 18-base-pair repeat element. J Virol 63:1435, 1989. Fraile-Ramos A, Pelchen-Matthews A, Kledal TN, Browne H, Schwartz TW, Marsh M: Localization of HCMV UL33 and US27 in endocytic compartments and viral membranes. Traffic 3:218, 2002. Oldstone M: Molecular mimicry and immune-mediated diseases. FASEB J 12:1255, 1998.

Human Cytomegalovirus Molecular Mimicry

103. Alford C, Britt W: Cytomegalovirus. New York: Raven Press, 1990. 104. Varani S, Muratori L, De Ruvo N, Vivarelli M, Lazzarotto T, Gabrielli L, Bianchi FB, Bellusci R, Landini MP: Autoantibody appearance in cytomegalovirus-infected liver transplant recipients: Correlation with antigenemia. J Med Virol 66:56, 2002. 105. Soderberg C, Sumitrankaruppan S, Ljungman P, Moller E: CD13-specific autoimmunity in cytomegalovirus infected immunocompromised patients. Transplantation 61:594, 1996. 106. Soderberg C, Larsson S, Rozell BL, Sumitrankaruppan S, Ljungman P, Moller E: Cytomegalovirus-induced CD13-specific autoimmunity—a possible cause of chronic graft-versus-host disease. Transplantation 61:600, 1996. 107. Toyoda M, Galfayan K, Galera OA, Petrosian A, Czer LS, Jordan SC: Cytomegalovirus infection induces antiendothelial cell antibodies in cardiac and renal allograft recipients. Transpl Immunol 5:104, 1997. 108. Lunardi C, Bason C, Navone R, Millo E, Damonte G, Corrocher R, Puccetti A: Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med 6:1183, 2000. 109. Hiemstra HS, Schloot NC, van Veelen PA, Willemen SJ,

475

110.

111.

112.

113.

114.

115.

Franken KL, van Rood JJ, de Vries RR, Chaudhuri A, Behan PO, Drijfhout JW, Roep BO: Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase. Proc Natl Acad Sci U S A 98:3988, 2001. Benoist C, Mathis D: Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nat Immunol 2:797, 2001. Welsh R, Selin L: No one is naive: the significance of heterologous T-cell immunity. Nature Rev Immunol 2:417, 2002. Brehm M, Pinto A, Daniels K, Schneck J, Welsh R, LK S: T cell imunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. Nat Immunol 3:627, 2002. Toyoda M, Petrosian A, Jordan SC: Immunological characterization of anti-endothelial cell antibodies induced by cytomegalovirus infection. Transplantation 68:1311, 1999. Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L, Hsu ML: A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Cell 7:273, 1997. Reyburn HT, Mandelboim O, Valesgomez M, Davis DM, Pazmany L, Strominger JL: The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386:514, 1997.