Viruses and apoptosis

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1 Lawrence S Young, Christopher W Dawson and Aristides G Eliopoulos CRC Institute for Cancer Studies, University of Birmingham Medical School, Birmingham, UK Virus infection and replication are often associated with apoptosis and this effect is likely to be responsible for much of the pathology associated with infectious disease. Many viruses encode proteins which can inhibit apoptosis thereby either prolonging the survival of infected cells such that the production of progeny virus is maximised or facilitating the establishment of virus persistence.these viral proteins target the cellular pathways responsible for regulating apoptosis and have been instrumental in furthering our understanding of the apoptotic process. Many of the viruses associated with oncogenic transformation have adopted strategies for blocking apoptosis highlighting the centrality of this effect in carcinogenesis. Understanding the mechanisms by which viruses regulate apoptosis may lead to the development of novel therapies for both infectious disease and cancer. Correspondence fo. Prof Lawrence S Young, CRC Institute for Cancer Studies, University of Birmingham Medical School, Birmingham B75 2TJ, UK Apoptosis or programmed cell death is an actively controlled process of cell suicide characterised by distinctive morphological and biochemical changes 1. Regulation of apoptosis is essential for normal embryonic development and for homeostasis in adult tissues. This altruistic process is also important in eliminating cells whose survival might otherwise prove harmful to the organism as a whole, thereby providing a defense against viral infection and the development of cancer. Whilst virusinfected cells can often be recognised and destroyed by apoptotic processes initiated by either virus-specific cytotoxic T lymphocytes or certain cytokines, many viruses directly induce apoptosis during infection. Indeed, it is this virally-induced apoptosis that is considered to be at least partially responsible for the various pathologies associated with virus infection. Many viruses have evolved mechanisms to block the premature apoptosis of infected cells facilitating either the establishment and maintenance of persistent infection or prolonging the survival of lytically-infected cells such that the production of progeny virus is maximised (Table 1). Indeed, these viral anti-apoptotic strategies can also contribute to the pathogenesis of virus infection and, in extreme situations, promote the oncogenic capacity of certain viruses. Recent studies of the various mechanisms used by viruses to suppress apoptosis have shed light on the fundamental biochemical pathways responsible for regulating programmed cell death. Bntah Medical Bulletin 1997;53 (No 3) Th«Brituh Council 1997

2 Apoptoiis Table! Viral inhibitors of apoptosis Virus Gens product Function References Adenovirus E1B19K Bcl-2 homologue 1,67,13,14,17 EBV ASFV HHV-8 Adenovirus SV40 HPV CowpoX VMVt Boculo virus Boculo virus EBV BHRF1 LMW5-HL f E1B55K Large T antigen E6 crma p35 lap LMP1 Bd-2 homologue Bd-2 homologue Bd-2 homologue InoctTvation of p53 Inochvation of p53 InactivaKon of p53 ICE inhibitor ICE inhibitor ICE inhibitor Interacts with TRAFs Induces Bcl-2 in B calls Into rocts with TRAFs 22, ,7, ,33 32, ,37-40 The role of Bcl-2 and its viral homologues during virus infection Many viruses induce apoptosis upon infection of certain cell types but the precise mechanisms involved remain obscure. Bcl-2, the prototype inhibitor of apoptosis, can block the cell death induced by Sindbis virus thereby converting an acute lytic infection into a persistent infection 2. The apoptosis and concomitant cytopathic effects induced by acute influenza infection are also suppressed in the presence of Bcl-2 3. HIV infection of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines induces apoptosis apparently as a consequence of the downregulation in Bcl-2 expression 4. Thus, the modulation of endogenous Bcl-2 expression may influence the outcome of virus infection highlighting the Bcl-2 pathway as a potentially important target for viruses. It is, therefore, not surprising that certain DNA viruses have evolved specific virus genes with homology to Bcl-2 which are important in controlling the host cell response to virus infection. The adenovirus El A and E1B19K proteins Whilst adenovirus infection results in relatively benign infections in man, it is the ability of adenoviruses to transform primary cells in vitro that has provided a paradigm for understanding the cellular pathways involved in the deregulated cell growth associated with oncogenesis. Transformation of cells by adenoviruses type 2, 5 and 12 is dependent on the early region 1 portion of the viral genome which contains the transcription units for the E1A and E1B proteins 5. The E1A protein 510 Bnhih Medico/ Bulletin 1997,53 (No. 3)

3 activates resting cells into the cell cycle stimulating host cell DNA synthesis via diverse interactions with numerous cellular proteins including the retinoblastoma gene product prb 5. This creates a proliferative cellular environment in which viral DNA replication can occur. However, it was noted several years ago that infection with adenoviras mutants lacking the 19K protein encoded by the ElB region resulted in the degradation of both viral and host cell DNA leading to premature cell death 5. This effect has more recently been characterised as ElA-induced apoptosis occurring in the absence of a functional ElB 19K protein 6. In common with other apoptosis-inducing factors, ElA expression results m the accumulation of p53 and this response mediates the ability of ElA to induce apoptosis 7 ' 8. Thus, the outcome of ElA expression is dependent on the p53 status of cells and consequently mutant p53 blocks the induction of apoptosis by ElA 7 and ElA is able to transform p53-deficient mouse embryo fibroblasts 9. Furthermore, baby rat kidney (BRK) cells transformed by ElA and a temperaturesensitive p53 proliferate at the restrictive temperature when p53 is predominantly in the mutant conformation but undergo apoptosis at the permissive temperature when p53 is predominantly wild type 7. Thus, apoptosis may result from conflicting cell growth signals with ElA stimulating both cell proliferation and elevated p53 which inhibits cell cycle progression. This contention is supported by data demonstrating that the regions of ElA that function to induce cell proliferation cosegregate with those that are responsible for apoptosis and apoptosis is only induced by ElA when cell proliferation is inhibited 10. These effects of ElA resemble those of the c-myc protein which can induce apoptosis under conditions where proliferation is blocked 11. More recent work suggests a possible role for the transcription factor NF-KB in ElAinduced apoptosis 12. ElA-induced p53-mediated apoptosis is suppressed by products of the adenovirus ElB transcription unit. Two major protein products are encoded by this region, the ElB 19K or the ElB 55K proteins, and both of these proteins are able to block ElA-induced apoptosis and cooperate with ElA for complete growth transformation 6-7. The ElB 55K protein blocks the function of p53 s whilst the precise mechanism by which ElB 19K protein inhibits p53-mediated apoptosis remains unknown. However, the ElB 19K protein shares significant sequence and functional homology with Bcl-2 suggesting that these two proteins operate to inhibit apoptosis by similar mechanisms 6 ' In this regard, Bcl-2 can substitute for ElB 19K protein during adenovirus infection of human cells 14 and in the cooperation with ElA to transform rodent cells 6. Both ElB 19K and Bcl-2 proteins block p53-dependent apoptosis and can overcome the transcriptional repression activity of p53 J. Both proteins inhibit cell death induced by different apoptotic stimuli, including the Bnfis/iA<Wico/Bu//.tinl997;53(No 3) 511

4 Apoptosis cytotoxic drug cisplatin, tumour necrosis factor a (TNFa) and the Fas antigen although the ElB 19K protein appears to be more effective 1. Recent data show that ElB 19K can antagonise the stimulatory effect of E1A on NF-KB and similar effects on the activity of this transcription factor have been observed with Bcl In addition to the functional similarities between ElB 19K and Bcl-2, both these proteins are membrane-anchored, contain three short regions with sequence homology and interact with a common set of cellular proteins (Nipl,2,3) 13. A comparison of the amino acid sequence of Bcl-2 and ElB 19K revealed homology over a region of 19K known to be important for structure and function of the protein with particularly striking homology within the Bcl-2 homology region 1 (BH1), a functionally important domain required for heterodimerisation of Bcl-2 with another member of the Bcl-2 family, Bax 1 (Fig. 1). NH1 and NH2 have been identified as other regions of homology between ElB 19K and Bcl-2 and domain swapping studies between these proteins have emphasised the significance of the NH1 domain as a common functional domain in survival promoting members of the Bcl-2 family 17. Two cell death promoting members of the Bcl-2 family, Bik and Bak, have been identified by their interaction with ElB 19K and share another common domain designated BH3 which is also present in Bax Recent work demonstrates that the BH3 region of Bax mediates the interaction of Bax with ElB 19K and that this heterodimerisation inhibits p53-mediated apoptosis 20. In this scenario, the stabilisation of p53 in response to E1A expression or other stimuli results in the transcriptional activation of genes required for both growth arrest (p21/waf-l/cip-l) and death (Bax) with ElB 19K or Bcl-2 acting downstream of p53-mediated transactivation to overcome apoptosis induced by p53. The identification of specific domains such as BH3 which mediate the interaction of survival promoting Bcl-2 family members with Bax, Bik and Bak may be useful targets for the development of agents that can abrogate this interaction and thereby promote the apoptosis of virus-infected cells and of cancer cells. Epstein -Barr virus and the BHRFI protein Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus which is predominantly found as an asymptomatic persistent infection. However, under certain circumstances, EBV can contribute to the development of tumours of B cell origin (Burkitt's lymphoma, immunoblastic lymphoma) or of epithelial cell origin (nasopharyngeal carcinoma, gastric adenocarcinomas) 21. A unique characteristic of EBV is its ability to transform resting B lymphocytes in vitro into permanently growing 512 Bnh%h Medical Bullmtm 1997,53 (No 3)

5 BH3 BCL2 BHRFl ElB19k APQ AAAOF. HEANECLEDF SAVRNLLEQS SNSTi HH1 BH1 Fig. 1 Amino acid sequsncs homology between Bd-2, BHRFl and adenovirui5 E1B19K BCL2 BHRFl ElB19k proteins. Sequences were retrieved From the Gen Bank and EMBL data banks and alignments were performed using Pileup software. Gaps BCL2 BHRFl ElB19k OVM..v s VHREMSPL.. _STLCC NQSTPYYWD SFIKDKWsfs THLSO BH2 WRHKH made in individual sequences to optimize alignment are indicated by dots Identical residues or conservative changes are shown on a grey BCL2 BHRFl ElB19k.D. RLLLLSSVRP AX,YO. IQQQ LALVOAC ILTLSLL IPRE background.the Bcl-2 homology domains BH1, BH2 and BH3 and the E1B 19K homologous region 1 (NH1) are also shown "- 23 BCL2 BHRFl ElB19k ESR ORH lymphoblastoid cell lines in which every cell expresses a limited set of socalled virus latent proteins comprising a group of six nuclear antigens (EBNAs) and two membrane proteins (LMP1 and LMP2) 22. Apart from their coordinate role in the immortalisation of B cells, these latent proteins have also been implicated in the protection of B cells from apoptosis and thus may contribute to the persistence of EBV infection 23. The role of LMP1 in the regulation of apoptosis will be considered later. When EBV-infected cells enter the virus productive cycle, a cascade of additional EBV genes are expressed culminating in the lysis of the infected cell and release of progeny virus. One of the EBV proteins expressed during virus replication is BHRFl, an immediate early EBV antigen with sequence homology to Bcl-2 22 (Fig. 1). Although dispensable for both virus-induced cell growth transformation in vitro and virus replication 22, BHRFl has a proven ability to act as a cell survival gene. EBV-negative Burkitt lymphoma cells expressing BHRFl are rendered more resistant to apoptosis under experimental conditions of growth factor withdrawal and rodent hamster fibroblasts expressing BHRFl display increased resistance to the apoptotic inducing effects of British Mtdical Bulletin (No 3) 513

6 Apoptosis DNA-damaging drugs and of a mutant adenovirus defective in the ElB 19K protein 24 ' 25. These studies suggest that whilst BHRFl is not consistently expressed in EBV-associated tumours, it is possible that expression of this protein at an early stage in the oncogemc process may influence the development of these malignancies. To date, the only in vivo lesion where BHRFl is abundantly expressed is oral 'hairy' leukoplakia (HL), a benign lesion of oral tongue mucosa which represents a focus of chronic EBV replication with absence of detectable latent gene expression 21. Our recent data demonstrating that BHRFl can delay the terminal differentiation of epithelial cells through the prevention of apoptosis suggests that this protein may be responsible for HL pathology but may normally function to delay cell death during EBV replication, so that full virus maturation can occur 26. Like Bcl-2 and ElB 19K, the BHRFl protein predominantly localises to mitochondrial membranes, interacts with a common set of cellular proteins (Nip 1,2,3), and via binding to Bik can suppress the death promoting activity of this Bcl-2 family member 13 ' 18. Recent work indicates that BHRFl does not heterodimerise with Bax but can interact with p23 R-Ras, a member of the ras superfamily that has previously been shown to interact with Bcl The R-Ras binding region of BHRFl and the other domains of limited homology with Bcl-2 (i.e. BH1, BH2, NH1, etc.) are conserved amongst a range of different EBV isolates as is the anti-apoptotic function of this viral protein (Khanim and Young, submitted). BHRFl mutants which are unable to bind R-Ras retain the ability to suppress p53- dependent apoptosis but also display a gain of function phenotype which results in cell proliferation and more efficient co-operation with El A in BRK transformation assays 27. The proliferation-restraining activity of BHRFl could be inaaivated by spontaneous mutation or by expression of BHRFl in cells which are R-Ras negative and this may lead to the proliferation of cells otherwise destined for apoptosis, thereby contributing to EBV-induced oncogenesis. The ability of BHRFl to block apoptosis in both lymphoid and epithelial cells may be important in promoting the survival of EBV-infected cells that enter into the virus productive cycle, so that full virus replication and maturation can occur. Thus, BHRFl expression in Bcl-2-negative suprabasal epithelial cells or in Bcl-2-negative B lymphocytes may be an important requirement for the efficient production and release of mature EBV virions. Other virus-encoded regulators of apoptosis Apart from the viral homologues of Bcl-2, a number of viruses have adopted different strategies to inhibit apoptosis. Thus, viral proteins 514 Bnhsh Medical Bulletin 1997J3 (No 3)

7 have been identified which impinge on specific biochemical pathways involved in apoptosis and these have proved extremely useful in dissecting the apoptotic machinery. The targets for these viral proteins can be divided into three main groups which will be briefly considered. Modifiers of the p53 pathway Given the central role of p53 in growth arrest and apoptosis induced by many different stimuli, it is not surprising that viral proteins have evolved which block the function of p53. The adenovirus E1B 55K protein and the large T antigen of SV40 virus directly interact with p53 leading to the stabilisation of the protein with consequent inhibition of its transcriptional activity 28. The E6 proteins of the oncogemc human papillomaviruses (HPV) also bind to p53 but, rather than stabilising the protein, this interaction results in the rapid degradation of p53 through the ubiquitin-directed pathway 28. Thus, the small DNA tumour viruses (HPV, SV40, adenovirus) have all developed strategies to overcome the growth restraining and apoptosis-inducing properties of p53 and this effect contributes to the ability of these viruses to transform cells. The hepatitis B virus oncoprotein HBx, the IE84 protein from human cytomegalovirus and the EBNA5 protein from EBV have all been described as able to interact with p53 and inhibit its normal function 22 * 29. Recent work using either the SV40 large T antigen or HPV16 E6 to disable p53 function have highlighted the existence of p53-independent apoptotic pathways responsible for mediating cell death in response to genotoxic agents 30. Virus-encoded ICE inhibitors Another mechanism used by viruses to block apoptosis is the inhibition of the interleukin-l(3 converting enzyme (ICE) family of cysteine proteases which have been shown to play a central role in apoptosis. The crma gene of cowpox virus is a potent and specific inhibitor of ICElike proteases and can protect cells against apoptosis induced by growth factor withdrawal, Fas antigen engagement or cytotoxic T lymphocytes (CTL) 31. The insect baculoviruses contain a p35 gene which also inhibits ICE family proteases and blocks apoptosis in insect, nematode and mammalian cells Recombinant baculoviruses lacking the p35 gene induce accelerated cell death leading to severely impaired virus production 32. Unlike crma, the p35 inhibitor has a broader specificity for the ICE-like cysteine proteases but has no effect on granzyme B, a Bnhih Mtdxat Buffrtm 1997^3 (No 3) 515

8 Apoptosis serine protease responsible for CTL-induced apoptosis 33. The presence of an ICE inhibitor-encoding gene in the genome of an insect virus emphasises the significance of the ICE pathway as an evolutionary conserved regulator of apoptosis. Viral proteins and the TNF receptor pathway Another gene encoded by different members of the baculovirus family is IAP (inhibitor of apoptosis) which can protect against apoptosis in both insect and mammalian cells Mammalian homologues of IAP have recently been identified and, like the baculovirus IAPs, contain an N- terminal baculovirus IAP repeat (BIR) motif and a C-terminal zinc binding RING finger domain The IAPs can interact with a family of TNF receptor associated factors (TRAFs) which mediate signal transduction through the cytoplasmic domain of certain members of the TNF receptor superfamily The TRAFs also carry RING finger domains and their regulation of TNF receptor signalling may be modified by interaction with IAPs. Baculovirus-encoded IAP and certain mammalian IAPs appear to protect against ICE-induced apoptosis 35. Thus, rather than binding to and inhibiting ICE proteases, it may be that IAPs are involved in regulating receptor-mediated signals that are required for the processing and activation of cysteine proteases. The LMP1 protein of EBV is oncogenic in rodent fibroblasts and induces phenotypic changes in human B lymphocytes characteristic of activated cells including induction of DNA synthesis and up-regulation of various cell surface activation markers and adhesion molecules 22. LMP1 is essential for the in vitro growth transformation of B cells. Stable LMP1 expression can enhance the survival of B cells in response to serum withdrawal or p53-induced apoptosis through up-regulation of Bcl The induction of Bcl-2 expression by LMP1 is not observed in epithelial cells where stable LMP1 expression also results in phenotypic changes, including the inhibition of terminal differentiation The ability of LMP1 to activate the transcription factor NF-KB is responsible for many of its phenotypic effects including the induction of the A20 zinc finger protein which affords protection from the cytotoxic effects of TNF-a 22. Fiigh level expression of LMP1 can induce growth arrest and apoptosis and the regions of the protein responsible for this effect coincide with those that are required for rodent cell transformation Many of the effects induced by LMP1 resemble those observed in response to stimulation of B cells or epithelial cells through the TNF receptor or CD40, another member of the TNF receptor family. It is, therefore, not surprising that the cytoplasmic carboxy terminus of LMP1 516 British Mtdical Bull»hn 1997,53 No 3}

9 interacts with members of the TRAF family, thereby impinging on the same biochemical pathways activated by TNF receptor or CD40 signalling 22. Our recent work demonstrates that LMP1 expression inhibits epithelial cell growth in a manner mimicked by CD40 ligation and that this effect is partly mediated by TRAF3 40. This inhibition of epithelial cell growth by LMP1 or through CD40 sensitises cells to subsequent apoptosis induced by cytotoxic drugs, TNF-a, Fas or ceramide. Thus, the effect of LMP1 on cell growth and apoptosis depends on the level and stability of LMP1 expression and on the cellular environment. HIV and apoptosis Infection by the HIV (human immunodeficiency virus) retrovirus leads to acquired immune deficiency syndrome (AIDS). Early events following HTV infection include functional defects of T cells, characterised by the inability of T cells to proliferate in vitro in response to T cell receptor (TcR) stimulation, followed by loss of CD4 + and the decline of CD8 + T cells with the onset of ADDS. It has been proposed that the loss of CD4 + T cells in HTV-infected patients is a result of inappropriate induction of apoptotic cell death. Indeed, there is increasing evidence which now suggests that apoptosis induced by HTV is central to the pathogenesis of AIDS 41. Thus, freshly isolated T cells from HTV-infected but not from healthy individuals undergo spontaneous and activation-mediated apoptosis. This phenomenon may also occur in vivo, as high levels of CD4 + and CD8 + T cell death have been observed in lymph nodes of HTVinfected patients. More importantly, although a significant correlation between CD4 + T cell depletion and apoptosis has been reported in a number of different animal models of AIDS, apoptosis is not seen in chimpanzees, where viral replication does not result in AIDS. It, therefore, appears that HTV infection results in CD4 + T cell apoptosis both in vitro and in vivo and that this is a major factor in the development of AIDS. In addition to infected T lymphocytes, HTV may induce apoptosis in uninfected CD4 + T cells via an indirect mechanism. This could explain the dramatic loss of CD4 + T lymphocytes in HTV patients despite the fact that only a small percentage of peripheral blood mononuclear cells are actively infected. In this context it is also known that HTV can induce cell death in the absence of infection in cell types other than T cells, including neurons and haemopoietic progenitors in the bone marrow. Two main mechanisms have been proposed for HFV-induced apoptosis in uninfected T lymphocytes 42. Firstly, engagement of the Bnft.hM.cf.ca/Bulletin 1997;33 (No. 3) 517

10 Apoptosis CD4 molecule on the surface of uninfected T cells by the HIV env proteins expressed on the surface of infected macrophages and CD4 + T cells has been proposed to result to apoptosis. Indeed, CD4 cross-linking by anti-cd4 antibodies can induce apoptosis in uninfected CD4 + T cells both in vitro and in vivo and anti-env antibodies have been shown to block induction of apoptosis in response to HIV infection in vitro. Alternatively, it has been proposed that env-mediated crosslinking of CD4 induces expression and secretion of soluble Fas ligand (FasL) from uninfected CD4 + T cells and macrophages, which could then promote apoptosis in bystander lymphocytes via a Fas-FasL interaction. Fas is a type I membrane protein belonging to the TNF receptor family 43. It is expressed in a wide range of tissues and its ligation by certain monoclonal antibodies or FasL provides a rapid apoptotic response. The importance of the Fas/FasL interaction in regulating normal immune responses was revealed by the demonstration that the lymphoproliferative diseases in Ipr/lpr and gld/gld mice can be attributed to defects in the genes encoding Fas and FasL, respectively. Interestingly, whilst in vivo engagement of CD4 by specific anti-cd4 antibodies causes depletion of CD4 + T cells in normal mice, lymphocytes from Ipr/lpr mice are not affected 44, suggesting that CD4 cross-linking primes or induces apoptosis in a Fas-dependent manner. In this context, it has been shown that CD4 cross-linking may up-regulate Fas expression in T lymphocytes. The significance of Fas/FasL interaction in AIDS is endorsed by the observations that T lymphocytes from HTV-infected individuals show high levels of Fas expression and are more susceptible to Fas-mediated apoptosis 45. HTV-infected human macrophages also show elevated levels of expression of Fas and, interestingly, FasL 46. Overall, it appears that the depletion of CD4 + T cells by HIV may involve both direct and indirect pathways. Thus, CD4 cross-linking by the HIV env proteins may induce apoptosis of CD4 + T cells directly or may provide a stimulatory signal for Fas-mediated cell death. Conclusions Virus infection and replication commonly result in apoptosis and this effect may be responsible for much of the pathology associated with infectious disease. Viruses have adopted diverse strategies for inhibiting apoptosis and, thereby, prolonging the life of the infected cell, such that virus replication, spread and persistence is maximised. These strategies target the cellular pathways that mediate and regulate apoptosis and thus the viral proteins have proved useful in dissecting the biochemical mechanisms of cell death. In this context, it is interesting that diverse 518 Bnhti.M«dK:a/6u//«hn 1997^3 (No 3)

11 cellular and viral factors which result in growth inhibition and apoptosis (TNFa, CD40 stimulation, expression of E1A or LMP1) also activate the NF-KB transcription factor and that these effects are antagonised by survival promoting Bcl-2 family members such as Bcl-2, adenovirus E1B 19K and EBV BHRFl«,i5,i«(Eliopoulos and Young, unpublished observations). Viral homologues of Bcl-2 have also been identified in African swine fever virus and the newly described Kaposi's sarcomaassociated human herpesvirus 8 47>48. It is likely that other viral proteins which can modulate host apoptotic responses will be identified and these will continue to help in elucidating the pathways governing apoptosis. The regulation of apoptosis by viruses has also provided insight into oncogenic mechanisms and further understanding of these processes are likely to provide novel targets for cancer therapy. Acknowledgements Work performed in the authors' laboratory is supported by the Medical Research Council and the Cancer Research Campaign. References 1 White E. Life, death and the pursuit of apoptosis. Genes Dev 1996; 10: Levine B, Huang Q, Isaacs JT, Reed JC, Griffin DE, Hardwick JM. Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene Nature 1993; 361: Hinshaw VS, Olsen CW, Dybdahl-Sissoko N, Evans D. Apoptosis: a mechanism of cell killing by influenza A and B viruses / Virol 1994; de Rossi A, Ometto L, Roncella S et al. HTV-1 induced down-regulation of bcl-2 expression and death by apoptosis of EBV-immortalised B cells a model for a persistent 'self-limiting' HTV-1 infection. Virology 1994; 198: Shenk T Adenovindae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 3rd edn. Philadelphia: Lippincott-Raven, 1996: Rao LM, Debbas M, Sabbanni P, Hockenberry D, Korsmeyer S, White E. The adenovirus E1A proteins induce apoptosis which is inhibited by the E1B-19K and Bcl-2 proteins. Proc Natl Acad Sa USA 1992, 89: Debbas M, White E Wild type p53 mediates apoptosis by El A, which is inhibited by E1B. Genes Dev 1993; Lowe SW, Ruley HE Stabilization of p53 tumour suppressor is induced by adenovirus E1A and accompanies apoptosis. Genes Dev 1993; 7: Lowe SW, Jacks T, Housman DE, Ruley HE. Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc Natl Acad Set USA 1994; 91: Mymryk JS, Shire K, Bayley ST. Induction of apoptosis by adenovirus type 5 E1A in rat cells requires a proliferation block. Oncogene 1994; 9: Evan GI, Wyllie AH, Gilbert CS et al. Induction of apoptosis infibroblastsby c-myc protein Cell 1992; 69: Schmitz ML, Indorf A, Limbourg FP, Stadtler H, Traenckner EB, Baeuerle PA The dual effect of adenovirus type 5 E1A 13S protein on NF-KB activation is antagonized by E1B 19K. Mol Cell Biol 1996; 15: Bnh.hM.dica/BuHehn 1997^3 (No 3) 519

12 Apoptoiis 13 Boyd J, Malstrom S, Subramaruan T et al. Adenovirus E1B 19 kda and bcl-2 proteins interact with a common set of cellular proteins Cell 1994; Chiou SK, Tseng CC, Rao L, White E. Functional complementation of the adenovirus E1B 19K protein with Bcl-2 in the inhibition of apoptosis in infected cells. / Virol 1994; 68: Limbourg FP, Stadtler G, Chinnadurai G, Baeuerle PA, Schmitz ML A hydrophobic region of the adenovirus E1B 19 kda protein is necessary for the transient inhibition of NF-KB activated by different stimuli. / Biol Chem 1996; 271: Grimm S. Bauer MKA, Baeuerle PA, Schulze-Osthoff K. Bcl-2 down-regulates the activity of transcription factor NF-KB induced upon apoptosis. / Cell Btol 1996; 134: Subramman T, Boyd JM, Chinnadurai G. Functional substitution identifies a cell survival promoting domain common to adenovirus E1B 19 kda and Bcl-2 proteins. Oncogene 1995; 11: Boyd JM, Gallo GJ, Elanogovan B et al Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survivalpromoting proteins. Oncogene 1995; 11: Farrow SN, White JHM, Martmou I et al. Clomng of a bcl-2 homologue by interaction with adenovirus E1B 19K. Nature 1995; Han J, Sabbatini P, Perez D, Rao L, Modha D, White E The E1B 19K protein blocks apoptosis by interacting with and inhibiting the p53-inducible and death promoting Bax protein. Genes Dev 1996, 10: Rickinson AB, Kieff E. Epstein-Barr virus. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 3rd edn. Philadelphia: Lippincott-Raven, 1996: Kieff E. Epstein-Barr virus and its replication. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 3rd edn. Philadelphia: Lippincott-Raven, 1996: Gregory CD, Dive C, Henderson S et al. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature 1991; 349: Henderson S, Huen D, Rowe M, Dawson C, Johnson G, Rickinson A. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci USA 1993; Tarodi B, Subramanian T, Chinnadurai G. Epstein-Barr virus BHRF1 protein protects against cell death induced by DNA-damaging agents and heterologous viral infection. Virology 1994; 201: Dawson CW, Eliopoulos AG, Dawson J, Young LS. BHRF1, a viral homologue of the Bcl-2 oncogene, disturbs epithelial differentiation. Oncogene 1995; 9: Theodorakis P, D'Sa-Eipper C, Subramanian T, Chinnadurai G. Unmasking the proliferationrestraining activity of the anu-apoptosis protein EBV BHRF1. Oncogene 1996; 12: Nevins JR, Vogt PK. Cell transformation by viruses. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 3rd edn. Philadelphia: Lippincott-Raven, 1996: 301^43 29 Wang XW, Gibson MK, Vermeulen W et al. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene Cancer Res 1995; 55: Wahl AF, Donaldson KL, Fairchild C et al. Loss of normal p53 function confers sensinzation to taxol by increasing G2/M arrest and apoptosis. Nature Med 1996; 2: Kumar S. ICE-hke proteases m apoptosis. Trends Biol Sci 1995; 20: Clem RJ, Miller LK. Control of programmed cell death by the baculovirus genes p35 and lap. Mol Cell Btol 1994; 14: Bump NJ, Hackett M, Hugunin M et al. Inhibition of ICE family proteases by baculovirus annapoptoric protein p35. Science 1995; 269: Duckert CS, Nava VE, Gednch RW et al. A conserved family of cellular genes related to the baculovirus lap gene and encoding apoptosis inhibitors. EMBO ] 1996; 15: Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL. Cloning and expression of apoptosis inhibiting protein homologs that function to inhibit apoptosis and/or bind rumor necrosis factor receptor-associated factors. Proc Natl Acad Sa USA 1996; 93: Rothe M, Pan M-G, Henzel WJ, Ayres TM, Goeddel DV The TNFR2-TRAF signalling complex contains two novel proteins related to baculoviral inhibition of apoptosis proteins Cell 1995; BnhjJi Mednzal Bullmtm (No 3)

13 37 Henderson S, Rowe M, Gregory C et al. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protem 1 protects infected B cells from programmed cell death. Cell 1991; 65: Okan I, Wang Y, Chen F et al. The EBV-encoded LMP1 protein inhibits p53-tnggered apoptosis but not growth arrest. Oncogene 1995; 11: Lu JJ-Y, Chen J-Y, Hsu T-Y, Yu WCY, Su I-J, Yang CS. Induction of apoptosis in epithelial cells by Epstem-Barr virus latent membrane protem 1. / Gen Virol 1996; EJiopoulos AG, Dawson CW, Mosialos G et al. CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr virus-encoded LMP1: involvement of TRAF3 as a common mediator. Oncogene 1996; 13: Ameisen JC, Estaquier J, Idziorek T, DeBels F. The relevance of apoptosis to AIDS pathogenesis. Trends Cell Biol 1995; 5: Cohen DI, Taru Y, Tian H, Boone E, Samelson LE, Lane HC. Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1 Science 1992; 256: Lynch DH, Ramsdell F, Alderson MR. Fas and FasL in the homeostatic regulation of immune responses. Immunol Today 1995; 16: Wang ZQ, Dudhane A, Orlikowsky et al. CD4 engagement induces Fas antigen-dependent apoptosis of T cells in vivo Eur J Immunol 1994; 24: Katsikis PD, Wunderhch ES, Smith CA, Herzenberg LA, Herzenberg LA. Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virusinfected individuals / Exp Med 1995; 181: Badley AD, McElhinny JA, Leibson PJ, Lynch DH, Alderson MR, Paya CV. Up-regulanon of Fas hgand expression by human immunodeficiency virus in human macrophages mediates apoptosis of urunfected T lymphocytes. / Virol 1996; 70: Afonso CL, Neilan JG, Kutish GF, Rock DL. An African swme fever virus bcl-2 homolog, 5- HL, suppresses apoptotic cell death. / Virol 1996; 70: Sand R, Sato T, Bohenzky RA, Russo JJ, Moore PS, Chang Y. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) encodes a functional Bcl-2 homolog. Abstract st Herpesvirus Workshop, July 27 August , Illinois, USA BnhitiM«dx:o/B u //.f l n1997 ; 53(No 3) 521

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