and Immunity (2003) 4, 95–103 & 2003 Nature Publishing Group All rights reserved 1466-4879/03 $25.00 www.nature.com/gene Subversion of B signaling by infectious agents

P Hasler1 and M Zouali2 1Rheumatologische Universita¨tsklinik, Felix Platter-Spital, Burgfelderstrasse 101, Basel, Switzerland; 2Hoˆpital Broussais, INSERM U 430, Paris, France

Infectious agents and their hosts interact in a complex manner, involving not only superficially apparent mechanisms, but also the signaling machinery that governs cells responses. Thus, signaling events, surface molecule expression, and transcriptional control may be affected in various cell types, with profound consequences for the function of individual cells and organ systems. Studies of the biochemistry of cell signaling and cell invasion by infectious agents have begun to detail the interplay between elements of infectious organisms and the host at the molecular level. Consequently, the resulting interferences with lymphocyte signaling may disturb the function of the . In B cells, alterations of immune signaling has implications for human . By affecting the mechanisms of the host’s immune defense, this may not only lead to inadequate elimination of an infectious agent, but also to or neoplasia. Genes and Immunity (2003) 4, 95–103. doi:10.1038/sj..6363941

Keywords: B lymphocyte; signaling; infectious agent; EBV

Introduction B-lymphotropic herpes with a worldwide preva- lence of approximately 95%. Viral latent persistence As their hosts evolved mechanisms to thwart infection without apparent is a hallmark of EBV infection, and disease, infectious agents have adopted manifold and occurs in at least three forms characterized by the strategies to survive in their hosts and, eventually, to differential expression of six EBV nuclear cause disease. Antigenic shift of coat termed EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, 1 allows evasion from neutralizing . The ab- and EBNALP, and three integral latent membrane sence of viral presentation on the surface of proteins termed LMP1, LMP2A, and LMP2B. The neurons latently infected with virus expression of five of them (EBNA1, EBNA2, EBNA3a, 2 (HSV) and suppression of MHC class I expression by EBNA3c, and LMP1) is essential for immortalization of B 3,4 adenoviruses are examples of how may cells (reviewed in Refs.6,7). At least three of these EBV avoid recognition by T cells. Decreased expression of cell gene products have been shown to subvert B-lympho- adhesion molecules, as occurs with Epstein–Barr virus cyte signaling. EBV causes a broad variety of disorders, 5 (EBV) in Burkitt’s , may also compromise from infectious mononucleosis, a self-limiting lympho- T-cell interactions with infected target cells. More proliferative disease, to Burkitt’s lymphoma, Hodgkin’s recently, unsuspected mechanisms underlying subver- disease and, in immunocompromised individuals, im- sive effects of infectious agents have been identified. As munoblastic lymphoma, for example, AIDS-associated they bind to cell-surface molecules, even before gaining lymphoma. It is also associated with certain rare T-cell entry into cells, may disturb and subvert , poorly or nondifferentiated nasopharyngeal physiologic signaling. After cellular entry, they continue carcinoma, and epithelial oral .7 In vitro, to exploit molecules and signaling pathways of the host EBV has the propensity to transform and immortalize to ensure their survival and to promote their replication. B cells, allowing derivation of cell lines. It uses its major of viral components and release of infec- outer membrane gp350/220 to bind to CR2 tious particles further compromise cellular signaling. (CD21), the for the third comple- Here, we discuss the impact of interactions between ment component (C3d) and IFN-a.8 CD21 plays a major B and infectious agents on signal transduc- role in a signaling complex comprising sIgM,9 CD19,10 tion and on propagation. TAPA-1 (target of antiproliferative -1),10–12 and CD23.13 Interaction with cell-surface receptors Several other viral interactions with surface receptors critical for B-lymphocyte signaling critical for immune cell signaling have been identified. First, the receptor for is an integral membrane The best characterized interaction of an infectious agent protein with the conserved sequences and with B lymphocytes is that of EBV, a ubiquitous human domain structures characteristic of the immunoglobulin (Ig) superfamily.14 Second, although still controversial, it is thought that the IgA receptor may serve as a receptor Correspondence: Dr M Zouali, Institut de Recherches Biome´dicales des 15 Cordeliers, Unite´ d’Immunopathologie Humaine, Inserm U 430, 15 rue de for the hepatitis in humans. Third, the human I’Ecole de Me´decine, F-75006, Paris, France. signaling lymphocyte activation molecule (SLAM; also E-mail: [email protected] known as CDw150), which is expressed on B cells, T cells, Subversion of B lymphocyte signaling P Hasler and M Zouali 96 and dendritic cells, has been identified as a receptor recruitment of Syk and Lyn to the antiapoptotic serine– for surface binding and cell entry of mobilliform threonine kinase Akt constitutively induces the PI3-K viruses.16 In B cells, ligation of SLAM enhances activa- phosphorylation critical for Akt activation.33,36–38 By tion, proliferation, and Ig synthesis.17 Disturbance of phosphorylating and inactivating glycogen synthase these functions could account for the immunosuppres- kinase 3, activated Akt promotes cell survival by sion induced by the virus. Of additional interest nuclear accumulation of transcription factors that alter is that mutations of the SLAM-associated protein transcription.37 In addition, the proline-rich cytoplasmic (SAP, SHD1A, DSHP) are responsible for human regions of LMP2A bind multiple WW domains of the X-linked lymphoproliferative disease, in which absence E3 protein–ubiquitin ligases of the Nedd4 family to of the inhibitory properties of SAP is associated with form complexes that enhance Lyn and Syk ubiquitina- fulminant EBV infection.18 Fourth, entry of many strains tion in vivo and reduce levels of Lyn.39 The specificity of HSV is mediated by glycoprotein D, a structural of these effects of LMP2A, which are mediated by component of the HSV envelope that interacts with a clustering signal at the C-terminal domain of this a member of the tumor factor receptor molecule,40 has been demonstrated by the expression superfamily.19,20 Fifth, HIV-1 uses CD4 and of a mutant LMP2A, which, in contrast to wild-type receptors to infect target cells.21,22 LMP2A, allows the recruitment of Lyn, Syk, PI3-K, PLCg- Finally, the M-T7 protein functions as 2, Vav, Shc, and MAPK in response to BCR activation.33 a soluble homologue that can bind to and inhibit the Thus, LMP2A diverts Syk and Lyn from their physiologic biological activities of -gamma with high interactions, enhances the degradation of Lyn, and affinity in a species-specific manner.23 directs their activity toward a pathway that promotes cell survival. There is mounting evidence that other viruses also Pleiotropic consequences of cell subvert signaling through the BCR. The retroviral bovine receptor ligation virus causes a persistent increase in peripheral blood B-lymphocyte counts and, in some animals, Studies of EBV-immortalized B lymphocytes and of progression to B-cell leukemia and/or lymphoma. transgenic mouse models have led to the identification Recently, it was found that the B-cell protein tyrosine of a score of intricate subversive effects of this virus on phosphatase (PTPase) SHP-1 associates with the viral B-cell signaling. Upon gp350/220 ligation, CD21 caps transmembrane protein, gp30, indicating that gp30 acts together with sIgM, and the capped molecules and EBV as a decoy to sequester SHP-1.41 The removal of this particles are endocytosed into coated vesicles followed downregulatory PTPase could promote signaling by their release into the cytoplasm.24 HLA-DR MHC through the BCR, representing yet another mechanism class II molecules and a complex of three , for viral activation of B lymphocytes. gH, gL and gp42, of which the latter binds to HLA-DR, A similar phenomenon occurs in Kaposi sarcoma (KS)- also participate in this process.25 One effect of EBV associated herpesvirus (KSHV; also known as human binding to CD21 is activation of phosphatidyl-inositol 3- herpesvirus 8, HHV8) infection. In addition to causing kinase (PI3-K)26 and rapid activation of NF-kB via PI3-K, KS, the most frequent neoplasia in HIV-infected patients, PKC, and protein tyrosine kinases (PTKs).27 The activa- KSHV is closely linked to the B-cell lymphoproliferative tion ofNF-kB increases the expression of IL-1, IL-6, TNF- disorders such as primary effusion lymphoma and a, and IL-227,28 and mediates transcription of the viral plasmablastic, multicentric Castleman’s disease. In B latent gene promoter Wp.29 Thus, binding of EBV to B cells, its natural reservoir, KSHV expresses K1, a lymphocytes results in the removal of receptors from the transmembrane protein with a functional ITAM. Without cell surface, provides activation signals related to exogenous stimulation, K1 is able to initiate constitutive production, and leads to expression of the Ca2+ signaling and activation of Syk and PLCg-2.42 Other initial viral gene promoter Wp. Other potential effects, data indicate that K1 is responsible for low-grade lytic such as modification of CD21 binding of cytoplasmic p53 replication in vivo.43 A total of 10–15% of KSHV-positive and p68, and the nuclear p120 ribonucleoprotein,30 have plasmablasts express high levels of virally encoded IL-6 yet to be addressed in detail. (vIL-6),44 which may further enhance its pathogenic properties. Thus, K1-mediated signaling may participate Interference with normal B-cell in viral transcriptional activation and reactivation from latency, and drive the differentiation of KSHV-infected receptor signaling naive B cells into plasmablasts and toward lymphopro- A remarkable property of some viruses is to directly take liferative transformation. A close relative of KSHV, the advantage of signals normally arising from the B-cell rhesus monkey (RRV), a gamma-2 herpes- receptor (BCR). In the case of EBV, LMP2A aggregation virus, produces a transmembrane signaling protein, R1, in the plasma membrane of nonproliferating peripheral B that also promotes cell growth and transformation. Its cells disrupts BCR signaling (Figure 1a).31,32 It inhibits cytoplasmic domain contains several tyrosine residues Ca2+ influx and prevents physiologic tyrosine phosphor- whose phosphorylation by Syk elicits B-lymphocyte ylation by binding the PTKs Syk and Lyn.33 While activation similar to K1.45 Therefore, in each of these phosphorylation of LMP2A tyrosine 112 by Lyn enables cases, a single is capable of interfering with its association with this PTK,34 phosphorylation at signals normally arising from the BCR, and of targeting tyrosines 74 and 85 within the LMP2A immunoreceptor proximal or distal pathways to promote activation, cell tyrosine activation motif (ITAM) allows binding of Syk survival, latency and transformation. As will be dis- through the Syk tandem SH2 domains, and Syk tyrosine cussed below, these observations are probably relevant to phosphorylation and activation.35 Subsequently, LMP2A viral infection in vivo.

Genes and Immunity Subversion of B lymphocyte signaling P Hasler and M Zouali 97 a Normal signaling Blockade of BCR following BCR ligation signaling by LMP2A

mIg mIg

β α α β β α α β

CD79 CD79 Syk Lyn Lyn SyK PLC-γ1 Inhibition of tyrosine phosphorylation and Intracellular of Ca++ influx Ca++ release Activation of downstream effectors

Lyn Syk LMP2A

b Unligated CD40 CD40 Ligation Activation of LMP1 following primary infection by EBV

TRAF

TRAF 1 2 3 5 6

TRAF 1 2 3 5 6 TRAF 1 2 3 5 6

LMP1 TANK κ Activation of NF-κB and ERK Activation of NF- B and TRAF AP-1 transcription factors CD40 domain

Transmission of growth signals Figure 1 Model for the subversive effects of two EBV products on B-lymphocyte signaling. (a): Blocking activity of LMP2A on B-cell receptor signaling. Following BCR engagement, ITAMs on the a and b subunits of CD79 are tyrosine phosphorylated leading to the recruitment of the PTKs Lyn and Syk. Activated Syk induces PLC-g1 activation which triggers a series of signaling events, leading to intracellular Ca2+ release and, subsequently, to activation of downstream mediators. Through phosphorylation of tyrosines within its ITAM domain, LMP2A of EBV aggregates Lyn and Syk, preventing accumulation of tyrosine phosphorylated proteins and Ca2+ influx. Thus, by subverting normal BCR , LMP2A blocks switching from the latency stage to the lytic stage. (b) Activating effect of LMP1 on lymphocyte signaling through CD40. In the absence of CD40 ligation, TRAF molecules are bound to the cytoplasmic part of CD40. Following CD40 ligation, there is a trimerization of the three CD40 subunits and release of the TRAF molecules. Then, the TRAF family member associated NFk-B activator protein (TANK) heterodimerizes with some TRAFs, leading to activation of the NF-kB and ERK.104 LMP1 of EBV acts by binding certain TRAFs and activating NF-kB and AP1 transcription factors. Thus, it mimics the physiological B-cell activation events induced by CD40 engagement that normally lead to transmission of growth signals.

Genes and Immunity Subversion of B lymphocyte signaling P Hasler and M Zouali 98 Reminiscent of these subversive effects of viruses on Mimicking B-lymphocyte activation BCR signaling are the properties of some microbial signaling products. Bacteria produce many toxins that bind specifically to HLA class II molecules and certain Vb In addition to blocking physiologic BCR signaling and T-cell receptors. As a result of their capacity to stimulate substituting for a functional BCR, EBV can mimic a greater proportion of T lymphocytes than peptide physiologic signaling via CD40, a member of the tumor antigens without a requirement for processing, necrosis factor family of receptors (TNFR) that initiates they have been termed ‘T-cell superantigens’.46 It signaling by transmitting growth signals to the nucleus appears that some microbial products also target human through cytoplasmic TNFR-associated factors (TRAFs). B lymphocytes. They affect proliferation and Ig produc- This property is mediated by LMP1, an integral tion in response to antihuman IgM, and induce protein membrane protein expressed in latently infected B cells, tyrosine phosphorylation and activation of PLC and and oncogenic even in nonlymphoid cells.61 Structures PKC.47,48 Some of them, such as protein G of group C and shared with TNFRs allow LMP1 to emulate constitutive G streptococci, and protein H of Streptococcus pyogenes, activation of CD40 (Figure 1B) by activating the interact with specific portions of the Ig constant transcription factor NF-kB and binding to certain regions.49 Similarly, expression of Fc receptors by HSV- TRAFs.62 This is accompanied by binding of an NF-kB- 1 and 2, varicella–zoster virus and human CMV allows like factor to kB sequences within the A20 promoter to these viruses to directly interact with host Igs, to interfere induce expression of A20, an inducible zinc-finger with humoral immunity and to modify the host B-cell protein that enhances resistance to TNF-a cytotoxicity.63 response.50–52 Even more intriguing is the potential of The cytoplasmic C-terminus of LMP1 interacts with other infectious agents to produce molecules, referred TRAF2 and TRAF1, and binds to the p80 TNFR, CD40, to as ‘B-cell superantigens’,49,53 capable of interacting and the lymphotoxin-b receptor, while a different EBV- specifically with the Ig H- or L-chain variable regions, induced protein, EB16, associates with the p80 TNFR64 to independent of the binding site. This group of activate NF-kB by aggregation with TRAF-1 and À2.65 microbial products, which includes protein A of Staphy- This is compatible with the finding that LMP1 activation lococcus aureus, gp120 of HIV-1, protein L of Peptostrepto- of NF-kB is not dependent on the sequences mediating coccus magnus (reviewed in Ref.54), can trigger a cascade signal propagation of the p55 TNFR or on interaction of signaling events, with PTK and PLC stimulation and, with receptor-interacting protein (RIP).66 ultimately, activation of MAP kinase.55 In experimental Thus, by acting like a constitutively activated TNFR, animals, one B-cell superantigen was shown to have LMP1 emulates activation signals triggered by CD40 profound effects on B lymphocytes in both neonatal and signaling.67 Furthermore, proliferation of EBV-trans- adult mice.56 Additional studies are required to elucidate formed B cells requires continuous expression of LMP1, the signaling pathways that lead to such extensive B-cell in a manner resembling CD40-CD154-induced B-cell alterations. activation via NF-kB and c-Jun terminal kinase (JNK) signaling.67 Likewise, in addition to the TRAF interaction domain of LMP1, a distinct C -terminal domain activates the JNK pathway and the AP-1 transcription factor.68 Substituting for the absence of a Other B-cell effector functions induced by oligomeriza- functional BCR tion of the 200 carboxyl terminal residues of LMP1, such as rescue from BCR-mediated growth arrest, and secre- To survive, developing B cells must avoid elimination at tion of Ig and IL-6, are practically identical to those several checkpoints, including the requirement for arising in response to CD40 signaling.69 There is also successful IgH-chain rearrangements and BCR assembly. evidence that a C-terminal region of LMP1 initiates JAK As discussed above, in the absence of a functionally phosphorylation, implying modification of STAT signal- competent BCR, LMP2A provides in vitro constitutive ing by EBV.70 Conversely, LMP1 originating from EBV- survival signals for mature B cells. Not unexpectedly, infected cells is capable of suppressing activation of in vivo transgenic expression of LMP2A enables B-cell T cells and inducing T-cell anergy, a paradox that awaits progenitors to survive censoring for successful rearran- full explanation.71 gement and expression of functionally viable IgH- chains.57 Even the loss of sIg expression caused by LMP2A, an alteration expected to result in rapid Subversion of early- and ,58 fails to prevent cell survival and prolifera- late-signaling events tion.59 Consequently, nontransformed cells lacking pre-BCR and BCR expression predominate in the Another strategy of modifying signaling by substituting bone marrow and periphery of LMP2A transgenic for physiologic factors is used by the African swine fever mice.57 The specificity of LMP2A activity was confirmed virus (ASFV) that causes a highly contagious, hemor- by the absence of developmental abnormalities or rhagic disease in pigs with extensive B-cell loss and survival phenotypes in EmLMP2ABCRÀ transgenic mice nonspecific hypergammaglobulinemia. This may be expressing a mutant LMP2A ITAM.60 Thus, LMP2A explained by the downregulation of surface CD21, and allows B-cell survival and development in the absence by the severe apoptosis of B cells, unless they are rescued of physiologic signals under the condition that its by CD40L expressed on activated T cells.72 This activity ITAM is functional. Because LMP2A can substitute for may be related to the presence of A238L, a viral protein antigen drive in mature B lymphocytes, it is probably with sequence similarities to IkB. On the one hand, it important for the virus to gain access to the memory acts like cyclosporin by binding to calcineurin, which B-cell pool. stabilizes A238L,73 and by inhibiting dephosphorylation

Genes and Immunity Subversion of B lymphocyte signaling P Hasler and M Zouali 99 and nuclear translocation of NFAT.74 On the other hand, B-cell differentiation and may favor the development of A238L dissociates NF-kB from IkB by activating the AIDS-associated B-cell lymphomas.79 This may be NF-kB pathway, leading to a rapid physiologic degrada- caused by modulation of cyclin-dependent kinase activ- tion of IkB. A238L itself can then bind to the free p65 ity or by prolonged survival of B cells, NF-kB, effectively blocking NF-kB signaling owing to the probably by interfering with the DNA-binding activity of insensitivity of the resulting dimer to activation.75 NF-kB. That A238L protein is able to modulate NF-kB activity in vitro suggests an important role in . However, deletion of this protein has no effect on the Transcriptional modulation of ability of ASFV to replicate in vitro or in vivo.20,76 As in B-lymphocyte gene expression other circumstances, many of the ‘‘immune evasion’’ genes have only been characterized in vitro, and very few EBV drives B cells to proliferate through the expression examples exist of subversive genes that have definitively of nine latent proteins under the control of the been shown to play a role in viral pathogenesis. transcription factor EBNA2.80 By acting as a transcrip- Similar subversive properties have also been identified tional modulator of cellular and viral gene expression, in retroviral infection targeting B lymphocytes. First, EBNA2 plays a pivotal role in B-cell immortalization. It B cells from mice with MAIDS, a -induced activates the transcription of CD21 and CD2381 and the acquired syndrome, show an early PTK c-Fgr,82 and downregulates expression of the IgH- IgM-signaling alteration and a generalized defect in chain locus.83 Importantly, EBNA2 interacts with the B-cell proliferative responses.77 Apart from alterations transcription factor RBP-J, a protein highly conserved in multiple tyrosine phosphorylation events, there is a in evolution F from nematodes to humans F that acts reduction of Ca2+ influx, an impaired tyrosine phosphor- downstream of the receptor Notch.84 In Drosophila, Notch ylation response to IgM crosslinking or to PMA plus Ca2+ is expressed throughout development and influences cell ionophore. Second, Abl/myc- and raf/myc-containing fate decisions. Notch homologs isolated from vertebrates, subvert JAK-STAT signaling, resulting in including mice and humans, play a role in cell-type in vitro loss of IL-7 dependence, and pre-B-cell transfor- determination at multiple steps of differentiation, parti- mation, and in B-cell tumors in BALB/c mice.78 Third, cularly in the hematopoietic system.85,86 For example, soluble Tat, a biologically active extracellular protein Notch signaling affects the maturation of ,87 released by infected cells in HIV-positive patients, affects the choice between CD4 and CD8 T cells,88 and between

Table 1 Signaling targets of infectious agents in B lymphocytes

Infectious agent Active molecule Signaling effect Consequences on B lymphocytes Ref.

Epstein–Barr virus LMP2A Interference with Syk and Lyn Promotion of cell survival 33 Disruption of signaling Retroviral bovine leukemia gp30 Sequestration of SHP-1 Cell activation 41 virus Human herpesvirus 8 K1 transmembrane protein Activation of Syk andPLCg-2 Differentiation and 42 transformation Rhesus monkey rhadinovirus R1 transmembrane protein Interference with Syk Cell activation 45 Staphylococcus aureus Protein A Activation of PTK, PLC, and Cell expansion and, then, death 55,56 MAP kinase Epstein–Barr virus LMP1 Binding to certain TRAFs Emulation of CD40 signaling 65,67 Activation of NF-kB Oncogenic effect African swine fever virus A238L viral protein with Blocking of NF-kB signaling Cell death 72,73 similarities to IkB

MAIDS Unknown Alterations in multiple early Defect in proliferative 77 signaling events responsiveness

Retroviruses Abl/myc Interference with JAK-STAT Tumors 78 signaling Raf/myc HIV-1 Tat Modulation of cyclin-dependent Cell differentiation and, possibly, 79 kinase activity cell lymphomas Epstein–Barr virus EBNA2 Transcription of CD21, CD23, Cell immortalization 81À84 and c-Fgr Interacts with the transcription factor RBP-J Downregulates expression of the IgH-chain locus

Genes and Immunity Subversion of B lymphocyte signaling P Hasler and M Zouali 100 a/b vs g/d T-cell lineages.89 Recently, it was shown that other effects, disrupts BCR signaling as well as antigen the intracellular domain of Notch1 is active in B cells and internalization.96 LMP1 also associates with rafts, from that it participates in gene regulation in a manner similar which it links to the cytoskeleton via a TRAF-interacting to that of EBNA2.90 Therefore, EBNA2, which is domain.97 Even for HIV-1, the infectious potential consistently expressed in the naive IgD+ B-cell subset depends on intact lipid rafts.98 of healthy tonsils,91 may be regarded as a functional Finally, the subversion of B-lymphocyte signal trans- homolog of activated Notch. The molecular mechanisms duction by infectious agents deserves consideration with underlying transcriptional regulation and its functional respect to the critical role of signaling in autoimmunity.99 consequences in B lymphocytes remain the focus Mounting evidence indicates that a tight control of of investigation. Recently, the EBV BART (BamHI-A signaling pathways and highly coordinated interactions rightward transcript) RPMS1 has been found to of several transmembrane and cytosolic proteins are encode for a protein that colocalizes with Notch1C and required for appropriate signaling through the BCR to EBNA2 and negatively regulates EBNA2 and Notch1 avoid overt autoimmunity. In as much as infectious signaling.92 agents alter signaling by interacting with signaling molecules that critically guide optimal immune self–nonself discrimination, it is conceivable that Conclusions EBV and other agents interfere with normal signaling and disrupt the balance of normal B-lymphocyte signal- It is remarkable that persisting infectious agents have a ing. The cumulative effect of faulty signaling because predilection to affect the nervous and the immune of latently persisting, highly prevalent infectious systems. For example, lymphocytes can be infected with agents may complement, or even outweigh, the genetic a number of viruses, including , EBV, background in causing autoimmune disease. Such a HHV-6, HHV-8, adenoviruses, HIV and human T-cell scenario is compatible with the implication of infectious leukemia viruses 1 and 2. While the relative isolation of agents in human autoimmune diseases100,101 (reviewed in the nervous system from the immune system may favor Refs. 102,103). A more complete understanding of the persistence of infectious agents in that location, subvert- subverted pathways may provide the basis for targeted ing the immune system itself offers manifold opportu- therapies of diseases related to infection, perhaps includ- nities for pathogens to ensure their survival and ing autoimmune diseases. persistence. Thus, it is not surprising that the observa- tions detailed above show that infectious agents target a variety of molecules and B-lymphocyte signal transduc- tion pathways, in order to avoid detection and destruc- Acknowledgements tion, and to shift the outcome of infection to their advantage (Table 1). We thank Dr Ingemar Ernberg (Karolinska Institute, From the point of view of the immune system, the Stockholm) for critical comments. MZ is supported by ´ interaction between the mammalian host and infectious the Institut National de la Recherche et de la Sante ´ agents has, throughout evolution, shaped an array of Medicale (INSERM, Paris, France) and by grants from ´ defenses against the continuous assault by pathogens. the Fondation pour la Recherche Medicale (Paris), Reciprocally, from their point of view, infectious agents Agence Nationale de Recherche sur le SIDA (ANRS, have developed efficient strategies to survive and persist Paris) and Ensemble contre le SIDA (SIDACTION, Paris). in the infected host.93 In the case of EBV, subversion of B-cell signaling releases B lymphocytes from the con- straints of T-cell help, accessory molecule costimulation, References cytokine dependence for growth and proliferation, and inhibitory , while disallowing anergy and 1 Narayan O, Griffin DE, Chase J. Antigenic shift of visna virus programmed cell death. HHV-8 is another example of in persistently infected sheep. 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