SGM Journals
Review Article

A time to kill: viral manipulation of the cell death program

Stewart Hay, George Kannourakis

  • The Fiona Elsey Cancer Research Laboratory, Cancer Research Centre, School of Science, University of Ballarat, St John of God Hospital, 1002 Mair Street, Ballarat, Victoria 3350, Australia1
  • Author for correspondence: George Kannourakis. Fax +61 353 334 813. e-mail g.kannour{at}ballarat.edu.au

    • Journal of General Virology 2002; 83(7):1547–1564

    PubMed

    Abstract

    Many viruses have as part of their arsenal the ability to modulate the apoptotic pathways of the host. It is counter-intuitive that such simple organisms would be efficient at regulating this the most crucial pathway within the host, given the relative complexity of the host cells. Yet, viruses have the potential to initiate or stay the onset of programmed cell death through the manipulation of a variety of key apoptotic proteins. It is the intention of this review to provide an overview of viral gene products that are able to promote or inhibit apoptotic death of the host cell and to discuss their mechanisms of action. It is not until recently that the depth at which viruses exploit the apoptotic pathways of their host has been seen. This understanding may provide a great opportunity for future therapeutic ventures.

    Introduction

    Programmed cell death (PCD), as its name suggests, is an orchestrated biochemical process that leads ultimately to the demise of the cell. Included under this title of PCD are three broad categories by which a cell may die. Firstly and most typically is apoptosis, characterized frequently by chromatin condensation, phosphatidlyserine exposure, cytoplasmic shrinkage, membrane blebbing and caspase activation. Secondly, in a process quite analogous, is ‘apoptosis-like PCD’, which presents with some of the apoptotic features but lacks the densely packed chromatin. The third category is ‘necrosis-like PCD’, which is typified by the general absence of chromatin condensation but is distinguished from necrosis (death resulting from injury) through its use of a signalling pathway (Leist & Jaattela, 2001⇓ ; Shi, 2001⇓ ; Tilly, 2001⇓ ). Apoptosis is the best-characterized form of PCD. It is a crucial component for normal multicellular life, playing a key role in development and immunity.

    It is natural to expect viruses to have the ability to affect the apoptotic process within a host cell. This expectation is likely, given that, constitutively, virus survival is dependent upon the effective exploitation of the existing cellular machinery. Indeed, a virus can benefit and may instigate either promotion or inhibition of apoptosis, but often these parasites are greatly harmed by the natural apoptotic action elicited by the host. In response to a virus infection, the host produces an array of proteins, including cytokines and proteases. It utilizes the action of macrophages, natural killer cells, cytotoxic and helper T cells, neutrophils and B cells. Furthermore, in the infected site itself, the cells may respond through the swift signalling potential of interferon (IFN) (Roulston et al., 1999⇓ ; Stark et al., 1998⇓ ). Undoubtedly, it is a significant achievement for a virus to make its way through the intricate defence network of the host to establish an infection.

    Collectively, apoptotic pathways contain many individual steps. A virus may need to influence only a single point of the process to affect the onset or progress of the natural cell death program. There are, however, strategies other than simple biochemical manipulation that viruses use to overcome the hindering effects of apoptosis. A virus may multiply rapidly to produce many virions before an effective immune response can be mounted. This approach is exhibited by most RNA viruses, including vesicular stomatitis virus and influenza virus (Koyama, 1995⇓ ; Kurokawa et al., 1999⇓ ). Another strategy available to viruses is that of a cryptic infection. In this situation, a virus may infect a cell and remain undetected, thus avoiding host cell destruction and allowing a productive infection (Di Rosa & Barnaba, 1998⇓ ; Paroli et al., 2000⇓ ).

    Although the benefits to a virus in avoiding the apoptotic process are obvious, the onset of PCD is, in some cases, also advantageous. In such situations, the apoptotic demise of a cell results in the formation of small membrane-bound entities known as apoptotic bodies. These bodies pinch off from the dying cell and are consumed by the phagocytic action of neighbouring cells. This engulfment provides a means for the dissemination of the virus without initiating a concomitant host response, which would follow the release of the progeny into the extracellular fluid (Teodoro & Branton, 1997a⇓ ). This was shown in a recent study involving an adenovirus vector that proliferated in human cancer cell lines (Mi et al., 2001⇓ ). The vector sensitized the infected cells to recombinant tumour necrosis factor (TNF)-α-mediated PCD by the expression of dominant–negative I-κB. The results showed that, while apoptosis during viral DNA replication was detrimental to the proliferation of the virus, apoptosis after virion assembly enabled its dissemination. Electron microscopy showed the occurrence of virus within the apoptotic bodies or associated with them. This later induction of apoptosis also allowed for the spread of infection and subsequent regression in subcutaneous tumours or liver metastases (Mi et al., 2001⇓ ). Viruses are clearly sophisticated in their strategies for dissemination. In addition to the modulation of the apoptotic pathways, they may also bud from present and future contact points with other cells, further facilitating the spread of infection (Johnson & Huber, 2002⇓ ).

    It is believed that viruses that manipulate the apoptotic pathways have captured and modified the cellular machinery that regulates the host cell death pathways (McFadden et al., 1998⇓ ). The selective pressure for these types of survival promoting alterations would be immense and the advantage would be immediate.

    It is not uncommon for a single virus to encode proteins that function to both promote and inhibit apoptotic death. Human immunodeficiency virus type 1 (HIV-1) is such a virus. Its arsenal is formidable in its duality and in its potentiality. HIV Nef is able to induce apoptosis by way of the signalling pathway; it mediates an increased expression of TNF on the cell surface while also downregulating MHC class I and CD4 expression (Lama & Ware, 2000⇓ ). HIV Tat is also able to induce death by the extrinsically mediated pathway through increased expression of Fas (CD95) (Li-Weber et al., 2000⇓ ). However, other mechanisms by which Tat is able to induce apoptosis have been published (Bonavia et al., 2001⇓ ; New et al., 1998⇓ ; Park et al., 2001⇓ ). In addition, the effect of Tat in vivo is questionable to some degree given the incidence of abnormally high concentrations used experimentally. HIV also utilizes gp120/gp41 and Vpr for its pro-apoptotic imperatives. The gp120/gp41 is a complex derived from the envelope region of the retrovirus genome. The resulting complex cross-links to CD4 lymphocytes and induces apoptosis (Laurent-Crawford et al., 1993⇓ , 1995⇓ ; Sylwester et al., 1997⇓ ). The mechanism used by Vpr remains somewhat enigmatic. It is known that this protein can induce cell cycle arrest in the G2 phase and that this induction is related to the promotion of apoptosis (Chang et al., 2000⇓ ; Conti et al., 2000⇓ ; Patel et al., 2000⇓ ; Stewart et al., 1997⇓ ; Zhu et al., 2001⇓ ). Opposing this death effect are GPx, glutathione peroxidase, a protein that acts to reduce oxidative stress, and variants of the gag core protein p17–p24 that produce an antagonistic epitope effect and thereby inhibit apoptotic death via CD8+ leucocytes (Klenerman et al., 1994⇓ ; Zhao et al., 2000⇓ ).

    Indeed, data have been shown that the normally apoptotic proteins Tat and Vpr are able to evade the death sequence by elevating internal Bcl-2 levels and by interrupting the T cell receptor (TCR)-mediated apoptotic process, respectively (Ayyavoo et al., 1997⇓ ; Fukumori et al., 1998⇓ ; McCloskey et al., 1997⇓ ; Zauli et al., 1993⇓ ). Moreover, the effect of Tat when expressed exogenously has been demonstrated to inhibit the TNF-related apoptosis-inducing ligand (TRAIL)-mediated death pathway (Gibellini et al., 2001⇓ ). It is hypothesized that the dual internal function of Tat and Vpr may act to regulate the stages of virus infection. These factors may indeed play an important role in the chronology of virus replication and the subsequent apoptotic cell demise during infection (Conti et al., 2000⇓ ). Overall, HIV serves as a striking example for the depth of complexity often seen within these ‘simple’ organisms. Clearly, the effective exploitation of the apoptotic pathway, above all other cell processes, is a determining factor in virus survival.

    Tables 1⇓ and 2⇓ incorporate some of the known pro-apoptotic and anti-apoptotic factors produced by viruses. Here, the virus mechanisms for manipulating apoptosis are discussed.

    Table 1. Viruses that produce apoptosis-inducing proteins

    Table 2. Viruses that produce apoptosis-inhibiting proteins

    Signalling mediators (TNF and Fas)

    Initiation of the Fas and TNF apoptosis pathways occurs by the binding of receptor and ligand on the cell surface, resulting in the stimulation of a distinct cytoplasmic apoptosis pathway as shown in Fig. 1⇓. Often, this pathway is referred to as the ‘extrinsically mediated pathway’, apparently due to its external activation. From the point of initiation, viruses influence this pathway. Adenoviruses in particular have a direct influence at an early stage, with proteins E3-10.4K and E3-14.5K, which reduce the presentation of Fas molecules on the surface of the cell. This reduction of the apoptotic receptor results in a resistance to Fas-mediated cell death. The proteins 10.4K/14.5K also confer a protective effect against TNF-mediated apoptosis. However, in this case a loss of TNF surface expression is not responsible, indicating multiple cell death protecting qualities for this complex (Dimitrov et al., 1997⇓ ; Shisler et al., 1997⇓ ). Epstein–Barr virus (EBV) produces an anti-apoptotic protein named LMP-1 (latent membrane protein-1). This protein with its six membrane-spanning domains accumulates in the host cell plasma membrane. LMP-1 appears to be a constitutively activated TNF receptor, which is ligand-independent (Gires et al., 1997⇓ ). It has been shown that LMP-1 interacts with TNF-associated factors (TRAFs). TRAFs 1, 2 and 3 all bind to a site in the C-terminal domain between amino acids 199 and 214, a region known to be of significance for B cell growth transformation (Devergne et al., 1996⇓ ). In 1997, Izumi & Kieff (1997)⇓ also reported another site, TES2 (transformation effector site 2), which interacts with a TNF receptor-associated death domain protein (TRADD). Indeed, it utilizes TRADD in a signalling pathway in a manner similar to TNF receptor 1. The TES2 interaction with TRADD mediates a high-level activation of NFκB, in contrast to the association of TES1 with TRAFs, which only accounts for low-level NFκB activation (Devergne et al., 1996⇓ ; Eliopoulos et al., 1999⇓ ; Gires et al., 1997⇓ ; Izumi & Kieff, 1997⇓ ; Kusano & Raab-Traub, 2001⇓ ; Mosialos et al., 1995⇓ ; Roberts & Cooper, 1998⇓ ).

    Figure image not available in archive

    Fig. 1. The interaction of viral proteins with the apoptotic pathways of the host. Viral products promoting apoptosis are shown in green, whereas those inhibiting apoptosis are shown in red.

    The myxoma virus (MYXV) protein M-T2 is a virus mimic protein of the TNF receptor and is a potent inhibitor of extracellular TNF-mediated apoptosis. It is released in either a monomeric or a dimeric form and binds TNF, thus negating TNF receptor signal transduction. The protein also has an intracellular ability to suppress cell death in CD4+ T lymphocytes. This function is distinct to that of binding extracellular TNF and appears to be mediated by the first two cysteine-rich domains of the M-T2 protein (Barry & McFadden, 1998⇓ ; McFadden & Barry, 1998⇓ ; Schreiber et al., 1997⇓ ; Xu et al., 2000⇓ ). Cowpox virus (CPV) also has TNF receptor family-related proteins, the cytokine response-modifying (Crm) proteins CrmB, CrmC and CrmD. M-T2 has similarity to both CrmB and CrmD (Cunnion, 1999⇓ ). Until recently, it was unknown whether the C-terminal regions of the Crm proteins had TNF ligand-binding domains. It has now been shown that the vaccinia virus (VV) protein related to CrmC, A53R, is capable of producing a TNF-binding protein. This protein is soluble and able to bind TNF with high affinity, thus preventing the engagement of cell TNF receptors (Alcamı́ et al., 1999⇓ ).

    IFN pathway mediators

    A host response to virus infection includes the induction of apoptosis of the infected cell through the action of leucocytes. IFNs participate in this process. These proteins exhibit signalling potential and have the ability to modulate immune activity and cell proliferation (Balachandran et al., 2000⇓ ). However, it is the ability of these proteins to interfere with the apoptotic pathway that is of particular interest here. In this regard, IFN plays an important part of a hosts′ response to infection and it achieves this by effecting important cellular genes, such as the dsRNA-dependent serine/threonine protein kinase (PKR), resulting in the sensitization of the cell death machinery. Any stage in virus infection appears susceptible to its inhibitory capacity (Stark et al., 1998⇓ ). In effect, IFNs prime a cell to destruction through the FADD (Fas-associated death domain)-containing protein-dependent apoptotic pathway. Furthermore, IFN is able to prevent the replication of some viruses that circumvent the activation of this pathway, hence the cell avoids the death program altogether (Balachandran et al., 2000⇓ ; Ezelle et al., 2001⇓ ). The significance of IFN to the virus is clearly apparent. Yet, it is surprising that, given its central importance, we do not see more reports of manipulation of the IFN-mediated pathway by viruses – though perhaps this remains a matter of time.

    Nevertheless, both VV and herpes simplex virus (HSV) work to affect this pathway through PKR. This enzyme, along with RNase L, is a key player in the IFN-mediated apoptotic pathway. Both of these enzymes are activated by the dsRNA that is often produced during the course of a virus infection (Barry & McFadden, 1998⇓ ; Der et al., 1997⇓ ; Diaz-Guerra et al., 1997⇓ ; Kibler et al., 1997⇓ ). It has been shown that PKR and IFN sensitize cells through the FADD/caspase-8 pathway (Balachandran et al., 2000⇓ ). It is interesting that RNase L, though acting in a similar manner, functions separately from PKR in response to apoptotic stimuli. Similarly, RNase L shows an ameliorated response to dsRNA. It was, however, still able to induce death effectively in cells from PKR-deficient mice (Diaz-Guerra et al., 1997⇓ ).

    Recently, Ezelle et al. (2001)⇓ provided further evidence of virus interaction with the IFN pathway and they hypothesized that viruses target not only the IFN inducible genes but also effectors along the IFN pathway. This suggests that viruses could avoid apoptotic cell death while allowing the expression of primary IFN targets such as the otherwise integral antiviral protein PKR.

    Bcl-2-related proteins

    The Bcl-2 protein family has at least 15 members that have been identified in mammalian cells, with still more evident in viruses (Adams & Cory, 1998⇓ ; Chao & Korsmeyer, 1998⇓ ; Cory, 1994⇓ , 1995⇓ ; Strasser et al., 1997⇓ ). The members of this large family all contain at least one of the four conserved Bcl-2 homology domains, titled BH1 to BH4.

    Bcl-2 itself is an integral membrane protein located mainly on the outer membrane of the mitochondria (Yang et al., 1997⇓ ). It can prevent apoptosis mediated by some caspases, but not all (Sutton et al., 1997⇓ ). The Bcl-2 protein family is able to modulate the cytochrome c/Apaf-1/caspase-9 pathway by essentially regulating the liberation of cytochrome c (Kluck et al., 1997⇓ ; Yang et al., 1997⇓ ). The anti-apoptotic members such as Bcl-2 and Bcl-XL act to mitigate its release, while Bad, Bax, Bid and Bim move from other cellular organelles to the mitochondria in response to apoptotic stimuli where they encourage the release of the molecule (Gross et al., 1999⇓ ).

    Bcl-2-related proteins have a number of virus mimics. The E1B-19K protein of adenovirus is such a mimic. It has been shown to associate with and inhibit apoptosis induced by the pro-apoptotic Bcl-2 protein family members, such as Bak, Bik and Bax (Granville et al., 1998⇓ ; Rao et al., 1997⇓ ). The adenoviral protein also interacts with the nuclear lamin, an interaction that has been shown to be necessary for both the localization of E1B-19K and the inhibition of apoptosis (Barry & McFadden, 1998⇓ ; Rao et al., 1997⇓ ). This protein inhibits a specific form of Bax and, as a result, blocks the TNF-α-mediated death-signalling pathway. The caspase cascade is stopped upstream of caspase-9 but downstream of caspase-8 (Perez & White, 2000⇓ ).

    BHRF1, a 17 kDa EBV protein, also bears similarity to Bcl-2, in both its structure and its function (Fanidi et al., 1998⇓ ; Khanim et al., 1997⇓ ; Niedobitek et al., 1991⇓ ). BHRF1 has been shown specifically to bear 38% homology to the C-terminal portion of Bcl-2 and to bear the same ultra-structural localization while also being able to inhibit c-Myc-induced apoptosis (Fanidi et al., 1998⇓ ; Hickish et al., 1994⇓ ).

    Recently, another related protein was discovered from the same virus. This virus survival gene, BALF1, encodes a protein that suppresses apoptosis and is associated with Bax and Bak (Marshall et al., 1999⇓ ; Young et al., 1999⇓ ). Structural analysis of BALF1 reveals several regions that recommend it as a Bcl-2 protein family member. Significantly, this includes sequence similarity in the Bcl-2 homologous domains BH1 to BH4, a region known to be important for function. It is intriguing that BALF1 shows a closer relationship to Bcl-xl and Bcl-2 than between the known EBV-encoded Bcl-2-related protein BHRF1 (Marshall et al., 1999⇓ ).

    Caspase suppressors

    There are few identified virus caspase inhibitors, amongst those discovered are CPV CrmA, baculovirus IAP (inhibitor of apoptosis protein) and p35 and African swine fever virus (ASFV) product A224L/4CL. CrmA is a potent caspase-1/caspase-8 inhibitor (Muzio et al., 1996⇓ ; Zhou et al., 1997⇓ ). CrmA does have some inhibition qualities for other caspases but the effect is substantially diminished (Kamada et al., 1997⇓ ; Zhou et al., 1997⇓ ). On the other hand, baculovirus protein p35 is a wide-ranging caspase inhibitor, inhibiting mammalian caspases 1–4 and 7 (Barry & McFadden, 1998⇓ ; Miller, 1997⇓ ). Even though the caspase inhibition qualities differ between these virus agents, they share the ability to inhibit TRAIL-induced apoptosis (Suliman et al., 2001⇓ ).

    The other anti-apoptotic baculovirus protein is IAP. It has become the archetypal member for a protein family in a way similar to Bcl-2. Its members, though not all appearing to be involved in apoptosis, show between one and three baculovirus repeats (Ekert et al., 1999⇓ ). Mammalian proteins related to this viral protein that have been shown to have an inhibitory effect on apoptosis include XIAP, c-IAP1, c-IAP2 and survivin (Deveraux & Reed, 1999⇓ ). The ASFV gene A224L produces a viral IAP-related protein (Chacon et al., 1995⇓ ). This protein has been shown to interact with and suppress the activity of caspase-3 (Nogal et al., 2001⇓ ).

    Cell cycle manipulators

    Distinct from most other categories, the cell cycle regulators are comprised almost equally of apoptotic inhibitors and inducers. The large T antigen expressed by simian virus 40 (SV40) is a good example, having in itself, both qualities. The antigen binds the retinoblastoma tumour suppressor protein (pRb)/p107/p130, in addition to p53 (Barry & McFadden, 1998⇓ ). This antigen can suppress caspase-1-induced apoptosis in a p53-dependent fashion (Jung & Yuan, 1997⇓ ). However, apoptosis is also promoted by the large T antigen binding to pRb (Kolzau et al., 1999⇓ ). This binding of pRb allows an increase in the transcriptional activity of E2F through its liberation, which triggers expression of p73 (Iglesias et al.,⇓ 1998⇓ ). Furthermore, SV40 has also a small tumour antigen, which inhibits the apoptosis-inducing qualities of the large T antigen, although the mechanism by which it achieves this still remains unknown (Kolzau et al., 1999⇓ ).

    The pX protein of hepatitis B virus (HBV) is also able to bind p53 and regulate the cell cycle. The controlled expression of this protein acts to modulate p53-dependent apoptosis (Chirillo et al., 1997⇓ ; Elmore et al., 1997⇓ ; Kim et al., 1998⇓ ; Lin et al., 1997⇓ ). An increase in the production of pX induces apoptosis, while a decline inhibits apoptosis (Chirillo et al., 1997⇓ ; Elmore et al., 1997⇓ ; Kim et al., 1998⇓ ; Su & Schneider, 1997⇓ ). The pX protein associates with p53 in the cytoplasm and minimizes its movement to the nucleus, where it acts to transactivate p53-responsive genes. Adding complexity to the issue is that, in the absence of p53, pX acts to promote cell proliferation rather than cell death; this appears to be the result of its alternate function as an independent transcriptional coactivator (Barnabas et al., 1997⇓ ; Barry & McFadden, 1998⇓ ; Chirillo et al., 1997⇓ ; Elmore et al., 1997⇓ ; Kim et al., 1998⇓ ; Lin et al., 1997⇓ ; Su & Schneider, 1997⇓ ; Takada et al., 1997⇓ ).

    Oxidative stress regulators

    Oxidative stress is a well-established feature of apoptosis. Certainly, the production of reactive oxygen intermediates and the accumulation of oxidized cellular compounds play a role in cell death mediation (Buttke & Sandstrom, 1994⇓ ; McGowan et⇓ al., 1996⇓ ). In the cell, GPx manages the deleterious effects of these stressing agents. Yet, it has been shown that molluscum contagiosum virus (MOCV) is also able to encode a similar protein to this cellular selenoprotein (Shisler et al., 1998⇓ ). This protein apparently confers a survival advantage by inhibiting apoptosis. Transfection of the GPx gene, MC066L, into keratinocytes or HeLa cells inhibited apoptosis instigated by hydrogen peroxide or UV irradiation but not by TNF or Fas (Barry & McFadden, 1998⇓ ; Shisler et al., 1998⇓ ). More recently, however, it has been shown that HIV-1 produces the same active selenoprotein (Zhao et al., 2000⇓ ). Zhang et al. (1999)⇓ found through sequence database searching combined with structurally guided comparative sequence analysis that GPx molecules may be produced in a number of RNA viruses, including, HCV, coxsackievirus B3, HIV-2 and measles virus (Zhang et al., 1999⇓ ).

    Protein kinases

    US3, a viral gene encoding an anti-apoptosis protein, is a product of HSV that functions as a serine/threonine kinase to block virus-induced apoptosis. This enzyme phosphorylates serine/threonine within a specific arginine-rich consensus sequence (Leopardi et al., 1997⇓ ). The details of the phosphorylating action of US3 remain undetermined. It is known that US3 cooperates with US5 to suppress apoptosis. These proteins function to strongly inhibit apoptosis induced by the Fas receptor or UV irradiation. US5 appears to be more critical for the inhibition of Fas-mediated apoptosis than US3 (Jerome et al., 1999⇓ ).

    Transcriptional modifiers

    It is to be expected that if viruses were to possess the machinery necessary to effect matters of cell survival and cell death that they should have the means to regulate transcription. Papillomaviruses achieve this by synthesis of a protein, E2, which represses the transcription of the integrated gene for E6, and by another p53-reliant scheme, which results in G1 arrest and apoptosis (Desaintes et al., 1997⇓ ). Marek′s disease virus apparently works by controlling the transcription of apoptosis-related genes, for example, by the induction of bcl-2 and the repression of Bax (Barry & McFadden, 1998⇓ ; Liu et al., 1998⇓ ).

    Endoplasmic reticulum-targeting factor

    M-T4, the fourth MYXV gene, is a critical virulence factor for myxomatosis in infected rabbits. It has an unusual attribute in that it is specifically targeted back to the endoplasmic reticulum. The presence of a C-terminal RDEL sequence is thought to be a causative region for this transportation to the endoplasmic reticulum (Barry et al., 1997⇓ ). However, this region may not be solely responsible for protein movement (Hnatiuk et al., 1999⇓ ).

    Recently, rubella virus was shown to induce apoptosis via its capsid protein, which was also located in the endoplasmic reticulum. It has also been demonstrated that the apoptotic effect of the protein is not linked to the intra-organelle calcium capacity (Duncan et al., 2000⇓ ).

    Conclusion

    Virus regulation of the apoptotic cell death program is a highly developed process. Viruses have shown repeatedly throughout history their prowess at manipulating this integral pathway; a fact demonstrated the world over by virus epidemics such as AIDS, polio and smallpox. A virus may with relative ease enter a cell and inhibit apoptosis in a manoeuvre that allows it sufficient time to proliferate, disperse from the plasma membrane and to infect other cells. Conversely, though just as readily, a virus may infect a cell, induce it to die and then spread to neighbouring cells through the phagocytosis of the resulting apoptotic bodies, in the process minimizing an immune response. Viruses are able at their task. Collectively they have an arsenal of proteins for both defence and offence. In many ways, the cell in all its complexity may be viewed as a marionette to the virus. Although the virus may only have a genome of several 1000 bp, it still has the capacity to pull the most crucial of ‘strings’ in a host that dwarfs it in terms of size and genetic material.

    The selective pressure for the incorporation of survival promoting genetic alterations in a virus, such as the capture of Bcl-2-related genes would be enormous. However, the number of ways in which viruses manipulate the apoptotic mechanism must illustrate not only the selective advantage of such insertions but also the susceptibly of this crucial process to manipulation and corruption.

    Although viruses can cause tremendous harm, the recent advances in molecular biology herald an era where the genes from these parasites may be used to generate a panoply of potential therapeutic benefits. In such a case, proliferative diseases such as cancer may be aided by apoptotic genes derived from viruses and targeted to the multiplying cells, while degenerative diseases such as Alzheimer′s, Parkinson′s and Huntington′s diseases may similarly be treated with anti-apoptotic viral genes. Ideologically, the process seems quite simple but difficulties are apparent when details such as gene delivery, expression levels and the time of gene expression are considered (Kay et al., 2001⇓ ; Verma & Somia, 1997⇓ ). The genetic structure of a virus recommends itself for gene therapy given its inherent simplicity. The fact that viruses are naturally infective and naturally able to alter a cells course between life and death make them a good starting point. However, as more knowledge is gained about cellular systems, it is likely that we may borrow more heavily from the existing cellular repertoire or simply engineer more efficient vectors in the name of expediency. One argument in favour of virally derived gene therapies is that these systems have presumably undergone considerable recombination and selection throughout their history. Consequently, they represent an amalgam of elements effective in enhancing the infection of viral (and potentially other) genetic elements.

    Acknowledgments

    We thank Dr Simon Fenton, Dr Robert Thurman, Jenny West and Dr D. Purcell for critical review of the manuscript. This work was supported by CICA (Ballarat, Victoria, Australia) and a University of Ballarat Collaborative Research Scholarship.

    References

    1. Adams, J. M. & Cory, S. (1998). The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322-1326.
    2. Afonso, C. L., Neilan, J. G., Kutish, G. F. & Rock, D. L. (1996). An African swine fever virus Bc1–2 homolog, 5-HL, suppresses apoptotic cell death. Journal of Virology 70, 4858-4863.
    3. Alcamı́, A., Khanna, A., Paul, N. L. & Smith, G. L. (1999). Vaccinia virus strains Lister, USSR and Evans express soluble and cell-surface tumour necrosis factor receptors. Journal of General Virology 80, 949-959.
    4. Allsopp, T. E., Scallan, M. F., Williams, A. & Fazakerley, J. K. (1998). Virus infection induces neuronal apoptosis: a comparison with tropic factor withdrawal. Cell Death and Differentiation 5, 50-59.
    5. Ayyavoo, V., Mahboubi, A., Mahalingam, S., Ramalingam, R., Kudchodkar, S., Williams, W. V., Green, D. R. & Weiner, D. B. (1997). HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor κB. Nature Medicine 3, 1117-1123.
    6. Balachandran, S., Roberts, C. P., Kipperman, T., Bhalla, K. N., Compans, R. W., Archer, D. R. & Barber, G. N. (2000). α/β Interferons potentiate virus-induced apoptosis through activation of the FADD/caspase-8 death signalling pathway. Journal of Virology 74, 1513-1523.
    7. Barnabas, S., Hai, T. & Andrisani, O. M. (1997). The hepatitis B virus X protein enhances the DNA binding potential and transcription efficacy of bZip transcription factors. Journal of Biological Chemistry 272, 20684-20690.
    8. Barry, M., Hnatiuk, S., Mossman, K., Lee, S. F., Boshkov, L. & McFadden, G. (1997). The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is retained within the endoplasmic reticulum and is important for the productive infection of lymphocytes. Virology 239, 360-377.
    9. Barry, M. & McFadden, G. (1998). Apoptosis regulators from DNA viruses. Current Opinion in Immunology 10, 422-430.
    10. Bartz, S. R. & Emerman, M. (1999). Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8. Journal of Virology 73, 1956-1963.
    11. Benedict, C. A., Norris, P. S., Prigozy, T. I., Bodmer, J. L., Mahr, J. A., Garnett, C. T., Martinon, F., Tschopp, J., Gooding, L. R. & Ware, C. F. (2001). Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2. Journal of Biological Chemistry 276, 3270-3278.
    12. Bertin, J., Mendrysa, S. M., LaCount, D. J., Gaur, S., Krebs, J. F., Armstrong, R. C., Tomaselli, K. J. & Friesen, P. D. (1996). Apoptotic suppression by baculovirus P35 involves cleavage by and inhibition of a virus-induced CED-3/ICE-like protease. Journal of Virology 70, 6251-6259.
    13. Bertin, J., Armstrong, R. C., Ottilie, S., Martin, D. A., Wang, Y., Banks, S., Wang, G. H., Senkevich, T. G., Alnemri, E. S., Moss, B., Lenardo, M. J., Tomaselli, K. J. & Cohen, J. I. (1997). Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proceedings of the National Academy of Sciences, USA 94, 1172-1176.
    14. Bonavia, R., Bajetto, A., Barbero, S., Albini, A., Noonan, D. M. & Schettini, G. (2001). HIV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons. Biochemical and Biophysical Research Communications 288, 301-308.
    15. Borgatti, P., Zauli, G., Colamussi, M. L., Gibellini, D., Previati, M., Cantley, L. L. & Capitani, S. (1997). Extracellular HIV-1 Tat protein activates phosphatidylinositol 3 and Akt/PKB kinases in CD4+ T lymphoblastoid Jurkat cells. European Journal of Immunology 27, 2805-2811.
    16. Brun, A., Rivas, C., Esteban, M., Escribano, J. M. & Alonso, C. (1996). African swine fever virus gene A179L, a viral homologue of bcl-2, protects cells from programmed cell death. Virology 225, 227-230.
    17. Brun, A., Rodriguez, F., Escribano, J. M. & Alonso, C. (1998). Functionality and cell anchorage dependence of the African swine fever virus gene A179L, a viral bcl-2 homolog, in insect cells. Journal of Virology 72, 10227-10233.
    18. Bruschke, C. J., Hulst, M. M., Moormann, R. J., van Rijn, P. A. & van Oirschot, J. T. (1997). Glycoprotein Erns of pestiviruses induces apoptosis in lymphocytes of several species. Journal of Virology 71, 6692-6696.
    19. Buttke, T. M. & Sandstrom, P. A. (1994). Oxidative stress as a mediator of apoptosis. Immunology Today 15, 7-10.
    20. Cassady, K. A., Gross, M. & Roizman, B. (1998). The second-site mutation in the herpes simplex virus recombinants lacking the γ134.5 genes precludes shutoff of protein synthesis by blocking the phosphorylation of eIF-2α. Journal of Virology 72, 7005-7011.
    21. Chacon, M. R., Almazan, F., Nogal, M. L., Vinuela, E. & Rodriguez, J. F. (1995). The African swine fever virus IAP homolog is a late structural polypeptide. Virology 214, 670-674.
    22. Chang, L. J., Chen, C. H., Urlacher, V. & Lee, T. Z. (2000). Differential apoptosis effects of primate lentiviral Vpr and Vpx in mammalian cells. Journal of Biomedical Science 7, 322-333.
    23. Chao, D. T. & Korsmeyer, S. J. (1998). Bcl-2 family: regulators of cell death. Annual Review of Immunology 16, 395-419.
    24. Chirillo, P., Pagano, S., Natoli, G., Puri, P. L., Burgio, V. L., Balsano, C. & Levrero, M. (1997). The hepatitis B virus X gene induces p53-mediated programmed cell death. Proceedings of the National Academy of Sciences, USA 94, 8162-8167.
    25. Chou, J. & Roizman, B. (1992). The γ134.5 gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programmed cell death in neuronal cells. Proceedings of the National Academy of Sciences, USA 89, 3266-3270.
    26. Clem, R. J., Fechheimer, M. & Miller, L. K. (1991). Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 254, 1388-1390.
    27. Conti, L., Matarrese, P., Varano, B., Gauzzi, M. C., Sato, A., Malorni, W., Belardelli, F. & Gessani, S. (2000). Dual role of the HIV-1 Vpr protein in the modulation of the apoptotic response of T cells. Journal of Immunology 165, 3293-3300.
    28. Conzen, S. D., Snay, C. A. & Cole, C. N. (1997). Identification of a novel antiapoptotic functional domain in simian virus 40 large T antigen. Journal of Virology 71, 4536-4543.
    29. Cory, S. (1995). Regulation of lymphocyte survival by the bcl-2 gene family. Annual Review of Immunology 13, 513-543.
    30. Cory, S., Strasser, A., Jacks, T., Corcoran, L. M., Metz, T., Harris, A. W. & Adams, J. M. (1994). Enhanced cell survival and tumorigenesis. Cold Spring Harbor Symposia on Quantitative Biology 59, 365-375.
    31. Crook, N. E., Clem, R. J. & Miller, L. K. (1993). An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. Journal of Virology 67, 2168-2174.
    32. Cunnion, K. M. (1999). Tumor necrosis factor receptors encoded by poxviruses. Molecular Genetics and Metabolism 67, 278-282.
    33. Danen-van Oorschot, A. A., van der Eb, A. J. & Noteborn, M. H. (2000). The chicken anemia virus-derived protein apoptin requires activation of caspases for induction of apoptosis in human tumor cells. Journal of Virology 74, 7072-7078.
    34. Dbaibo, G. S. & Hannun, Y. A. (1998). Cytokine response modifier A (CrmA): a strategically deployed viral weapon. Clinical Immunology and Immunopathology 86, 134-140.
    35. Debbas, M. & White, E. (1993). Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes & Development 7, 546-554.
    36. Der, S. D., Yang, Y. L., Weissmann, C. & Williams, B. R. (1997). A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proceedings of the National Academy of Sciences, USA 94, 3279-3283.
    37. Desaintes, C., Demeret, C., Goyat, S., Yaniv, M. & Thierry, F. (1997). Expression of the papillomavirus E2 protein in HeLa cells leads to apoptosis. EMBO Journal 16, 504-514.
    38. Desaintes, C., Goyat, S., Garbay, S., Yaniv, M. & Thierry, F. (1999). Papillomavirus E2 induces p53-independent apoptosis in HeLa cells. Oncogene 18, 4538-4545.
    39. Deveraux, Q. L. & Reed, J. C. (1999). IAP family proteins: suppressors of apoptosis. Genes & Development 13, 239-252.
    40. Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. (1997). X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388, 300-304.
    41. Devergne, O., Hatzivassiliou, E., Izumi, K. M., Kaye, K. M., Kleijnen, M. F., Kieff, E. & Mosialos, G. (1996). Association of TRAF1, TRAF2, and TRAF3 with an Epstein–Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-κB activation. Molecular and Cellular Biology 16, 7098-7108.
    42. Di Rosa, F. & Barnaba, V. (1998). Persisting viruses and chronic inflammation: understanding their relation to autoimmunity. Immunological Reviews 164, 17-27.
    43. Diaz-Guerra, M., Rivas, C. & Esteban, M. (1997). Activation of the IFN-inducible enzyme RNase L causes apoptosis of animal cells. Virology 236, 354-363.
    44. Dimitrov, T., Krajcsi, P., Hermiston, T. W., Tollefson, A. E., Hannink, M. & Wold, W. S. (1997). Adenovirus E3-10.4K/14.5K protein complex inhibits tumor necrosis factor-induced translocation of cytosolic phospholipase A2 to membranes. Journal of Virology 71, 2830-2837.
    45. Djerbi, M., Screpanti, V., Catrina, A. I., Bogen, B., Biberfeld, P. & Grandien, A. (1999). The inhibitor of death receptor signalling, FLICE-inhibitory protein defines a new class of tumor progression factors. Journal of Experimental Medicine 190, 1025-1032.
    46. Dobbelstein, M. & Shenk, T. (1996). Protection against apoptosis by the vaccinia virus SPI-2 (B13R) gene product. Journal of Virology 70, 6479-6485.
    47. Duncan, R., Esmaili, A., Law, L. M., Bertholet, S., Hough, C., Hobman, T. C. & Nakhasi, H. L. (2000). Rubella virus capsid protein induces apoptosis in transfected RK13 cells. Virology 275, 20-29.
    48. Ekert, P. G., Silke, J. & Vaux, D. L. (1999). Caspase inhibitors. Cell Death and Differentiation 6, 1081-1086.
    49. Eliopoulos, A. G., Blake, S. M., Floettmann, J. E., Rowe, M. & Young, L. S. (1999). Epstein–Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. Journal of Virology 73, 1023-1035.
    50. Elmore, L. W., Hancock, A. R., Chang, S. F., Wang, X. W., Chang, S., Callahan, C. P., Geller, D. A., Will, H. & Harris, C. C. (1997). Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proceedings of the National Academy of Sciences, USA 94, 14707-14712.
    51. Everett, H., Barry, M., Lee, S. F., Sun, X., Graham, K., Stone, J., Bleackley, R. C. & McFadden, G. (2000). M11L: a novel mitochondria-localized protein of myxoma virus that blocks apoptosis of infected leukocytes. Journal of Experimental Medicine 191, 1487-1498.
    52. Ezelle, H. J., Balachandran, S., Sicheri, F., Polyak, S. J. & Barber, G. N. (2001). Analyzing the mechanisms of interferon-induced apoptosis using CrmA and hepatitis C virus NS5A. Virology 281, 124-137.
    53. Fanidi, A., Hancock, D. C. & Littlewood, T. D. (1998). Suppression of c-Myc-induced apoptosis by the Epstein–Barr virus gene product BHRF1. Journal of Virology 72, 8392-8395.
    54. Farrow, S. N., White, J. H., Martinou, I., Raven, T., Pun, K. T., Grinham, C. J., Martinou, J. C. & Brown, R. (1995). Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K. Nature 374, 731-733.
    55. Fromm, L., Shawlot, W., Gunning, K., Butel, J. S. & Overbeek, P. A. (1994). The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice. Molecular and Cellular Biology 14, 6743-6754.
    56. Fukumori, T., Akari, H., Iida, S., Hata, S., Kagawa, S., Aida, Y., Koyama, A. H. & Adachi, A. (1998). The HIV-1 Vpr displays strong anti-apoptotic activity. FEBS Letters 432, 17-20.
    57. Gibellini, D., Caputo, A., Celeghini, C., Bassini, A., La Placa, M., Capitani, S. & Zauli, G. (1995). Tat-expressing Jurkat cells show an increased resistance to different apoptotic stimuli, including acute human immunodeficiency virus-type 1 (HIV-1) infection. British Journal of Haematology 89, 24-33.
    58. Gibellini, D., Re, M. C., Ponti, C., Maldini, C., Celeghini, C., Cappellini, A., La Placa, M. & Zauli, G. (2001). HIV-1 Tat protects CD4+ Jurkat T lymphoblastoid cells from apoptosis mediated by TNF-related apoptosis-inducing ligand. Cellular Immunology 207, 89-99.
    59. Gil, J., Rullas, J., Alcamı́, J. & Esteban, M. (2001). MC159L protein from the poxvirus molluscum contagiosum virus inhibits NF-κB activation and apoptosis induced by PKR. Journal of General Virology 82, 3027-3034.
    60. Gires, O., Zimber-Strobl, U., Gonnella, R., Ueffing, M., Marschall, G., Zeidler, R., Pich, D. & Hammerschmidt, W. (1997). Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule. EMBO Journal 16, 6131-6140.
    61. Gooding, L. R., Elmore, L. W., Tollefson, A. E., Brady, H. A. & Wold, W. S. (1988). A 14,700 MW protein from the E3 region of adenovirus inhibits cytolysis by tumor necrosis factor. Cell 53, 341-346.
    62. Gooding, L. R., Ranheim, T. S., Tollefson, A. E., Aquino, L., Duerksen-Hughes, P., Horton, T. M. & Wold, W. S. (1991). The 10,400- and 14,500-dalton proteins encoded by region E3 of adenovirus function together to protect many but not all mouse cell lines against lysis by tumor necrosis factor. Journal of Virology 65, 4114-4123.
    63. Granville, D. J., Carthy, C. M., Yang, D., Hunt, D. W. & McManus, B. M. (1998). Interaction of viral proteins with host cell death machinery. Cell Death and Differentiation 5, 653-659.
    64. Gross, A., McDonnell, J. M. & Korsmeyer, S. J. (1999). BCL-2 family members and the mitochondria in apoptosis. Genes & Development 13, 1899-1911.
    65. Heise, C., Hermiston, T., Johnson, L., Brooks, G., Sampson-Johannes, A., Williams, A., Hawkins, L. & Kirn, D. (2000). An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nature Medicine 6, 1134-1139.
    66. Henderson, S., Rowe, M., Gregory, C., Croom-Carter, D., Wang, F., Longnecker, R., Kieff, E. & Rickinson, A. (1991). Induction of bcl-2 expression by Epstein–Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 65, 1107-1115.
    67. Henderson, S., Huen, D., Rowe, M., Dawson, C., Johnson, G. & Rickinson, A. (1993). Epstein–Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proceedings of the National Academy of Sciences, USA 90, 8479-8483.
    68. Hickish, T., Robertson, D., Clarke, P., Hill, M., di Stefano, F., Clarke, C. & Cunningham, D. (1994). Ultrastructural localization of BHRF1: an Epstein–Barr virus gene product which has homology with bcl-2. Cancer Research 54, 2808-2811.
    69. Hnatiuk, S., Barry, M., Zeng, W., Liu, L., Lucas, A., Percy, D. & McFadden, G. (1999). Role of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and viral pathogenesis. Virology 263, 290-306.
    70. Hu, S., Vincenz, C., Buller, M. & Dixit, V. M. (1997). A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. Journal of Biological Chemistry 272, 9621-9624.
    71. Iglesias, M., Yen, K., Gaiotti, D., Hildesheim, A., Stoler, M. H. & Woodworth, C. D. (1998). Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α. Oncogene 17, 1195-1205.
    72. Izumi, K. M. & Kieff, E. D. (1997). The Epstein–Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-κB. Proceedings of the National Academy of Sciences, USA 94, 12592-12597.
    73. Jan, J. T., Chatterjee, S. & Griffin, D. E. (2000). Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide. Journal of Virology 74, 6425-6432.
    74. Jerome, K. R., Fox, R., Chen, Z., Sears, A. E., Lee, H. & Corey, L. (1999). Herpes simplex virus inhibits apoptosis through the action of two genes, Us5 and Us3. Journal of Virology 73, 8950-8957.
    75. Jeurissen, S. H., Wagenaar, F., Pol, J. M., van der Eb, A. J. & Noteborn, M. H. (1992). Chicken anemia virus causes apoptosis of thymocytes after in vivo infection and of cell lines after in vitro infection. Journal of Virology 66, 7383-7388.
    76. Joe, A. K., Foo, H. H., Kleeman, L. & Levine, B. (1998). The transmembrane domains of Sindbis virus envelope glycoproteins induce cell death. Journal of Virology 72, 3935-3943.
    77. Johnson, D. C. & Huber, M. T. (2002). Directed egress of animal viruses promotes cell-to-cell spread. Journal of Virology 76, 1-8.
    78. Jung, Y. K. & Yuan, J. (1997). Suppression of interleukin-1β converting enzyme (ICE)-induced apoptosis by SV40 large T antigen. Oncogene 14, 1207-1214.
    79. Kamada, S., Funahasi, Y. & Tsujimoto, Y. (1997). Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death and Differentiation 4, 473-478.
    80. Kawanishi, M. (1997). Expression of Epstein–Barr virus latent membrane protein 1 protects Jurkat T cells from apoptosis induced by serum deprivation. Virology 228, 244-250.
    81. Kay, M. A., Glorioso, J. C. & Naldini, L. (2001). Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nature Medicine 7, 33-40.
    82. Kettle, S., Alcamı́, A., Khanna, A., Ehret, R., Jassoy, C. & Smith, G. L. (1997). Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1β-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1β-induced fever. Journal of General Virology 78, 677-685.
    83. Khanim, F., Dawson, C., Meseda, C. A., Dawson, J., Mackett, M. & Young, L. S. (1997). BHRF1, a viral homologue of the Bcl-2 oncogene, is conserved at both the sequence and functional level in different Epstein–Barr virus isolates. Journal of General Virology 78, 2987-2999.
    84. Kibler, K. V., Shors, T., Perkins, K. B., Zeman, C. C., Banaszak, M. P., Biesterfeldt, J., Langland, J. O. & Jacobs, B. L. (1997). Double-stranded RNA is a trigger for apoptosis in vaccinia virus-infected cells. Journal of Virology 71, 1992-2003.
    85. Kim, H., Lee, H. & Yun, Y. (1998). X-gene product of hepatitis B virus induces apoptosis in liver cells. Journal of Biological Chemistry 273, 381-385.
    86. Klenerman, P., Rowland-Jones, S., McAdam, S., Edwards, J., Daenke, S., Lalloo, D., Koppe, B., Rosenberg, W., Boyd, D., Edwards, A. and others (1994). Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature 369, 403–407.
    87. Kluck, R. M., Bossy-Wetzel, E., Green, D. R. & Newmeyer, D. D. (1997). The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275, 1132-1136.
    88. Kolesnitchenko, V., King, L., Riva, A., Tani, Y., Korsmeyer, S. J. & Cohen, D. I. (1997). A major human immunodeficiency virus type 1-initiated killing pathway distinct from apoptosis. Journal of Virology 71, 9753-9763.
    89. Kolzau, T., Hansen, R. S., Zahra, D., Reddel, R. R. & Braithwaite, A. W. (1999). Inhibition of SV40 large T antigen induced apoptosis by small T antigen. Oncogene 18, 5598-5603.
    90. Koyama, A. H. (1995). Induction of apoptotic DNA fragmentation by the infection of vesicular stomatitis virus. Virus Research 37, 285-290.
    91. Krajcsi, P., Dimitrov, T., Hermiston, T. W., Tollefson, A. E., Ranheim, T. S., Vande Pol, S. B., Stephenson, A. H. & Wold, W. S. (1996). The adenovirus E3-14.7K protein and the E3-10.4K/14.5K complex of proteins, which independently inhibit tumor necrosis factor (TNF)-induced apoptosis, also independently inhibit TNF-induced release of arachidonic acid. Journal of Virology 70, 4904-4913.
    92. Kurokawa, M., Koyama, A. H., Yasuoka, S. & Adachi, A. (1999). Influenza virus overcomes apoptosis by rapid multiplication. International Journal of Molecular Medicine 3, 527-530.
    93. Kusano, S. & Raab-Traub, N. (2001). An Epstein–Barr virus protein interacts with Notch. Journal of Virology 75, 384-395.
    94. Laherty, C. D., Hu, H. M., Opipari, A. W., Wang, F. & Dixit, V. M. (1992). The Epstein–Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor κB. Journal of Biological Chemistry 267, 24157-24160.
    95. Lama, J. & Ware, C. F. (2000). Human immunodeficiency virus type 1 Nef mediates sustained membrane expression of tumor necrosis factor and the related cytokine LIGHT on activated T cells. Journal of Virology 74, 9396-9402.
    96. Lara-Pezzi, E., Majano, P. L., Gomez-Gonzalo, M., Garcia-Monzon, C., Moreno-Otero, R., Levrero, M. & Lopez-Cabrera, M. (1998). The hepatitis B virus X protein up-regulates tumor necrosis factor α gene expression in hepatocytes. Hepatology 28, 1013-1021.
    97. Laurent-Crawford, A. G., Krust, B., Riviere, Y., Desgranges, C., Muller, S., Kieny, M. P., Dauguet, C. & Hovanessian, A. G. (1993). Membrane expression of HIV envelope glycoproteins triggers apoptosis in CD4 cells. AIDS Research and Human Retroviruses 9, 761-773.
    98. Laurent-Crawford, A. G., Coccia, E., Krust, B. & Hovanessian, A. G. (1995). Membrane-expressed HIV envelope glycoprotein heterodimer is a powerful inducer of cell death in uninfected CD4+ target cells. Research in Virology 146, 5-17.
    99. Law, L. M., Duncan, R., Esmaili, A., Nakhasi, H. L. & Hobman, T. C. (2001). Rubella virus E2 signal peptide is required for perinuclear localization of capsid protein and virus assembly. Journal of Virology 75, 1978-1983.
    100. Leist, M. & Jaattela, M. (2001). Four deaths and a funeral: from caspases to alternative mechanisms. Nature Reviews Molecular and Cellular Biology 2, 589-598.
    101. Leopardi, R., Van Sant, C. & Roizman, B. (1997). The herpes simplex virus 1 protein kinase US3 is required for protection from apoptosis induced by the virus. Proceedings of the National Academy of Sciences, USA 94, 7891-7896.
    102. Li, C. J., Friedman, D. J., Wang, C., Metelev, V. & Pardee, A. B. (1995). Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science 268, 429-431.
    103. Li, Y., Kang, J. & Horwitz, M. S. (1998). Interaction of an adenovirus E3 14.7-kilodalton protein with a novel tumor necrosis factor α-inducible cellular protein containing leucine zipper domains. Molecular and Cellular Biology 18, 1601-1610.
    104. Lin, Y., Nomura, T., Yamashita, T., Dorjsuren, D., Tang, H. & Murakami, S. (1997). The transactivation and p53-interacting functions of hepatitis B virus X protein are mutually interfering but distinct. Cancer Research 57, 5137-5142.
    105. Liu, J. L., Ye, Y., Lee, L. F. & Kung, H. J. (1998). Transforming potential of the herpesvirus oncoprotein MEQ: morphological transformation, serum-independent growth, and inhibition of apoptosis. Journal of Virology 72, 388-395.
    106. Livne, A., Shtrichman, R. & Kleinberger, T. (2001). Caspase activation by adenovirus e4orf4 protein is cell line specific and is mediated by the death receptor pathway. Journal of Virology 75, 789-798.
    107. Li-Weber, M., Laur, O., Dern, K. & Krammer, P. H. (2000). T cell activation-induced and HIV tat-enhanced CD95(APO-1/Fas) ligand transcription involves NF-κB. European Journal of Immunology 30, 661-670.
    108. Low, W., Harries, M., Ye, H., Du, M. Q., Boshoff, C. & Collins, M. (2001). Internal ribosome entry site regulates translation of Kaposi′s sarcoma-associated herpesvirus FLICE inhibitory protein. Journal of Virology 75, 2938-2945.
    109. Lowe, S. W. & Ruley, H. E. (1993). Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes & Development 7, 535-545.
    110. McCarthy, S. A., Symonds, H. S. & Van Dyke, T. (1994). Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53. Proceedings of the National Academy of Sciences, USA 91, 3979-3983.
    111. McCloskey, T. W., Ott, M., Tribble, E., Khan, S. A., Teichberg, S., Paul, M. O., Pahwa, S., Verdin, E. & Chirmule, N. (1997). Dual role of HIV Tat in regulation of apoptosis in T cells. Journal of Immunology 158, 1014-1019.
    112. Macen, J. L., Graham, K. A., Lee, S. F., Schreiber, M., Boshkov, L. K. & McFadden, G. (1996). Expression of the myxoma virus tumor necrosis factor receptor homologue and M11L genes is required to prevent virus-induced apoptosis in infected rabbit T lymphocytes. Virology 218, 232-237.
    113. McFadden, G. & Barry, M. (1998). How poxviruses oppose apoptosis. Seminars in Virology 8, 429-442.
    114. McFadden, G., Lalani, A., Everett, H., Nash, P. & Xu, X. (1998). Virus-encoded receptors for cytokines and chemokines. Seminars in Cell & Developmental Biology 9, 359-368.
    115. McGowan, A. J., Ruiz-Ruiz, M. C., Gorman, A. M., Lopez-Rivas, A. & Cotter, T. G. (1996). Reactive oxygen intermediate(s) (ROI): common mediator(s) of poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis. FEBS Letters 392, 299-303.
    116. Maldarelli, F., Sato, H., Berthold, E., Orenstein, J. & Martin, M. A. (1995). Rapid induction of apoptosis by cell-to-cell transmission of human immunodeficiency virus type 1. Journal of Virology 69, 6457-6465.
    117. Marcellus, R. C., Teodoro, J. G., Charbonneau, R., Shore, G. C. & Branton, P. E. (1996a). Expression of p53 in Saos-2 osteosarcoma cells induces apoptosis which can be inhibited by Bcl-2 or the adenovirus E1B-55 kDa protein. Cell Growth and Differentiation 7, 1643-1650.
    118. Marcellus, R. C., Teodoro, J. G., Wu, T., Brough, D. E., Ketner, G., Shore, G. C. & Branton, P. E. (1996b). Adenovirus type 5 early region 4 is responsible for E1A-induced p53-independent apoptosis. Journal of Virology 70, 6207-6215.
    119. Marshall, W. L., Yim, C., Gustafson, E., Graf, T., Sage, D. R., Hanify, K., Williams, L., Fingeroth, J. & Finberg, R. W. (1999). Epstein–Barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associates with Bax and Bak. Journal of Virology 73, 5181-5185.
    120. Messud-Petit, F., Gelfi, J., Delverdier, M., Amardeilh, M. F., Py, R., Sutter, G. & Bertagnoli, S. (1998). Serp2, an inhibitor of the interleukin-1β-converting enzyme, is critical in the pathobiology of myxoma virus. Journal of Virology 72, 7830-7839.
    121. Meyers, G., Saalmuller, A. & Buttner, M. (1999). Mutations abrogating the RNase activity in glycoprotein Erns of the pestivirus classical swine fever virus lead to virus attenuation. Journal of Virology 73, 10224-10235.
    122. Mi, J., Li, Z. Y., Ni, S., Steinwaerder, D. & Lieber, A. (2001). Induced apoptosis supports spread of adenovirus vectors in tumors. Human Gene Therapy 12, 1343-1352.
    123. Miller, L. K. (1997). Baculovirus interaction with host apoptotic pathways. Journal of Cellular Physiology 173, 178-182.
    124. Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C. & Kieff, E. (1995). The Epstein–Barr virus transforming protein LMP1 engages signalling proteins for the tumor necrosis factor receptor family. Cell 80, 389-399.
    125. Moss, B., Shisler, J. L., Xiang, Y. & Senkevich, T. G. (2000). Immune-defense molecules of molluscum contagiosum virus, a human poxvirus. Trends in Microbiology 8, 473-477.
    126. Murphy, A. M., Morris-Downes, M. M., Sheahan, B. J. & Atkins, G. J. (2000). Inhibition of human lung carcinoma cell growth by apoptosis induction using Semliki Forest virus recombinant particles. Gene Therapy 7, 1477-1482.
    127. Muzio, M., Chinnaiyan, A. M., Kischkel, F. C., O′Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J. D., Zhang, M., Gentz, R., Mann, M., Krammer, P. H., Peter, M. E. & Dixit, V. M. (1996). FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817-827.
    128. Neilan, J. G., Lu, Z., Afonso, C. L., Kutish, G. F., Sussman, M. D. & Rock, D. L. (1993). An African swine fever virus gene with similarity to the proto-oncogene bcl-2 and the Epstein–Barr virus gene BHRF1. Journal of Virology 67, 4391-4394.
    129. Neilan, J. G., Lu, Z., Kutish, G. F., Zsak, L., Lewis, T. L. & Rock, D. L. (1997). A conserved African swine fever virus IκB homolog, 5EL, is nonessential for growth in vitro and virulence in domestic swine. Virology 235, 377-385.
    130. New, D. R., Maggirwar, S. B., Epstein, L. G., Dewhurst, S. & Gelbard, H. A. (1998). HIV-1 Tat induces neuronal death via tumor necrosis factor-α and activation of non-N-methyl-d-aspartate receptors by a NFκB-independent mechanism. Journal of Biological Chemistry 273, 17852-17858.
    131. Niedobitek, G., Young, L. S., Lau, R., Brooks, L., Greenspan, D., Greenspan, J. S. & Rickinson, A. B. (1991). Epstein–Barr virus infection in oral hairy leukoplakia: virus replication in the absence of a detectable latent phase. Journal of General Virology 72, 3035-3046.
    132. Nogal, M. L., Gonzalez de Buitrago, G., Rodriguez, C., Cubelos, B., Carrascosa, A. L., Salas, M. L. & Revilla, Y. (2001). African swine fever virus IAP homologue inhibits caspase activation and promotes cell survival in mammalian cells. Journal of Virology 75, 2535-2543.
    133. Pan, H. & Griep, A. E. (1995). Temporally distinct patterns of p53-dependent and p53-independent apoptosis during mouse lens development. Genes & Development 9, 2157-2169.
    134. Park, I. W., Ullrich, C. K., Schoenberger, E., Ganju, R. K. & Groopman, J. E. (2001). HIV-1 Tat induces microvascular endothelial apoptosis through caspase activation. Journal of Immunology 167, 2766-2771.
    135. Paroli, M., Schiaffella, E., Di Rosa, F. & Barnaba, V. (2000). Persisting viruses and autoimmunity. Journal of Neuroimmunology 107, 201-204.
    136. Patel, C. A., Mukhtar, M. & Pomerantz, R. J. (2000). Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells. Journal of Virology 74, 9717-9726.
    137. Perez, D. & White, E. (2000). TNF-α signals apoptosis through a bid-dependent conformational change in Bax that is inhibited by E1B 19K. Molecular Cell 6, 53-63.
    138. Pugachev, K. V. & Frey, T. K. (1998). Rubella virus induces apoptosis in culture cells. Virology 250, 359-370.
    139. Randazzo, B. P., Tal-Singer, R., Zabolotny, J. M., Kesari, S. & Fraser, N. W. (1997). Herpes simplex virus 1716, an ICP 34.5 null mutant, is unable to replicate in CV-1 cells due to a translational block that can be overcome by coinfection with SV40. Journal of General Virology 78, 3333-3339.
    140. Rao, L., Modha, D. & White, E. (1997). The E1B 19K protein associates with lamins in vivo and its proper localization is required for inhibition of apoptosis. Oncogene 15, 1587-1597.
    141. Revilla, Y., Cebrian, A., Baixeras, E., Martinez, C., Vinuela, E. & Salas, M. L. (1997). Inhibition of apoptosis by the African swine fever virus Bcl-2 homologue: role of the BH1 domain. Virology 228, 400-404.
    142. Roberts, M. L. & Cooper, N. R. (1998). Activation of a ras-MAPK-dependent pathway by Epstein–Barr virus latent membrane protein 1 is essential for cellular transformation. Virology 240, 93-99.
    143. Roulston, A., Marcellus, R. C. & Branton, P. E. (1999). Viruses and apoptosis. Annual Review of Microbiology 53, 577-628.
    144. Sah, N. K., Taneja, T. K., Pathak, N., Begum, R., Athar, M. & Hasnain, S. E. (1999). The baculovirus antiapoptotic p35 gene also functions via an oxidant-dependent pathway. Proceedings of the National Academy of Sciences, USA 96, 4838-4843.
    145. Schneider, R., Unger, G., Stark, R., Schneider-Scherzer, E. & Thiel, H. J. (1993). Identification of a structural glycoprotein of an RNA virus as a ribonuclease. Science 261, 1169-1171.
    146. Schreiber, M., Sedger, L. & McFadden, G. (1997). Distinct domains of M-T2 the myxoma virus tumor necrosis factor (TNF) receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition. Journal of Virology 71, 2171-2181.
    147. Shi, Y. (2001). A structural view of mitochondria-mediated apoptosis. Nature Structural Biology 8, 394-401.
    148. Shisler, J., Yang, C., Walter, B., Ware, C. F. & Gooding, L. R. (1997). The adenovirus E3-10.4K/14.5K complex mediates loss of cell surface Fas (CD95) and resistance to Fas-induced apoptosis. Journal of Virology 71, 8299-8306.
    149. Shisler, J. L. & Moss, B. (2001). Molluscum contagiosum virus inhibitors of apoptosis: The MC159 v-FLIP protein blocks Fas-induced activation of procaspases and degradation of the related MC160 protein. Virology 282, 14-25.
    150. Shisler, J. L., Senkevich, T. G., Berry, M. J. & Moss, B. (1998). Ultraviolet-induced cell death blocked by a selenoprotein from a human dermatotropic poxvirus. Science 279, 102-105.
    151. Shtrichman, R. & Kleinberger, T. (1998). Adenovirus type 5 E4 open reading frame 4 protein induces apoptosis in transformed cells. Journal of Virology 72, 2975-2982.
    152. Shtrichman, R., Sharf, R., Barr, H., Dobner, T. & Kleinberger, T. (1999). Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requires an interaction with protein phosphatase 2A. Proceedings of the National Academy of Sciences, USA 96, 10080-10085.
    153. Skaletskaya, A., Bartle, L. M., Chittenden, T., McCormick, A. L., Mocarski, E. S. & Goldmacher, V. S. (2001). A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proceedings of the National Academy of Sciences, USA 98, 7829-7834.
    154. Slinskey, A., Barnes, D. & Pipas, J. M. (1999). Simian virus 40 large T antigen domain and Rb-binding motif are sufficient to block apoptosis induced by growth factor withdrawal in a neural stem cell line. Journal of Virology 73, 6791-6799.
    155. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. (1998). How cells respond to interferons. Annual Review of Biochemistry 67, 227-264.
    156. Stewart, S. A., Poon, B., Jowett, J. B. & Chen, I. S. (1997). Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest. Journal of Virology 71, 5579-5592.
    157. Strasser, A., Huang, D. C. & Vaux, D. L. (1997). The role of the bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumourigenesis and resistance to chemotherapy. Biochimica et Biophysica Acta 1333, F151-F178.
    158. Sturzl, M., Hohenadl, C., Zietz, C., Castanos-Velez, E., Wunderlich, A., Ascherl, G., Biberfeld, P., Monini, P., Browning, P. J. & Ensoli, B. (1999). Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi′s sarcoma spindle cells. Journal of the National Cancer Institute 91, 1725-1733.
    159. Su, F. & Schneider, R. J. (1997). Hepatitis B virus HBx protein sensitizes cells to apoptotic killing by tumor necrosis factor α. Proceedings of the National Academy of Sciences, USA 94, 8744-8749.
    160. Su, F., Theodosis, C. N. & Schneider, R. J. (2001). Role of NF-κB and myc proteins in apoptosis induced by hepatitis B virus HBx protein. Journal of Virology 75, 215-225.
    161. Suliman, A., Lam, A., Datta, R. & Srivastava, R. K. (2001). Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20, 2122-2133.
    162. Sutton, V. R., Vaux, D. L. & Trapani, J. A. (1997). Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes. Journal of Immunology 158, 5783-5790.
    163. Sylwester, A., Murphy, S., Shutt, D. & Soll, D. R. (1997). HIV-induced T cell syncytia are self-perpetuating and the primary cause of T cell death in culture. Journal of Immunology 158, 3996-4007.
    164. Takada, S., Kaneniwa, N., Tsuchida, N. & Koike, K. (1997). Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells. Oncogene 15, 1895-1901.
    165. Tarodi, B., Subramanian, T. & Chinnadurai, G. (1994). Epstein–Barr virus BHRF1 protein protects against cell death induced by DNA-damaging agents and heterologous viral infection. Virology 201, 404-407.
    166. Teodoro, J. G. & Branton, P. E. (1997a). Regulation of apoptosis by viral gene products. Journal of Virology 71, 1739-1746.
    167. Teodoro, J. G. & Branton, P. E. (1997b). Regulation of p53-dependent apoptosis, transcriptional repression, and cell transformation by phosphorylation of the 55-kilodalton E1B protein of human adenovirus type 5. Journal of Virology 71, 3620-3627.
    168. Tewari, M. & Dixit, V. M. (1995). Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus CrmA gene product. Journal of Biological Chemistry 270, 3255-3260.
    169. Thomas, M. & Banks, L. (1998). Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 17, 2943-2954.
    170. Thomas, M. & Banks, L. (1999). Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. Journal of General Virology 80, 1513-1517.
    171. Thompson, C. B. (1995). Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456-1462.
    172. Tilly, J. L. (2001). Commuting the death sentence: how oocytes strive to survive. Nature Reviews: Molecular Cell Biology 2, 838-848.
    173. Tsai, S. C., Pasumarthi, K. B., Pajak, L., Franklin, M., Patton, B., Wang, H., Henzel, W. J., Stults, J. T. & Field, L. J. (2000). Simian virus 40 large T antigen binds a novel Bcl-2 homology domain 3-containing proapoptosis protein in the cytoplasm. Journal of Biological Chemistry 275, 3239-3246.
    174. Tsukumo, S. I. & Yonehara, S. (1999). Requirement of cooperative functions of two repeated death effector domains in caspase-8 and in MC159 for induction and inhibition of apoptosis, respectively. Genes to Cells 4, 541-549.
    175. Turner, P. C., Sancho, M. C., Thoennes, S. R., Caputo, A., Bleackley, R. C. & Moyer, R. W. (1999). Myxoma virus Serp2 is a weak inhibitor of granzyme B and interleukin-1β-converting enzyme in vitro and unlike CrmA cannot block apoptosis in cowpox virus-infected cells. Journal of Virology 73, 6394-6404.
    176. Turner, S. J., Silke, J., Kenshole, B. & Ruby, J. (2000). Characterization of the ectromelia virus serpin, SPI-2. Journal of General Virology 81, 2425-2430.
    177. Verma, I. M. & Somia, N. (1997). Gene therapy: promises, problems and prospects. Nature 389, 239-242.
    178. Viswanath, V., Wu, Z., Fonck, C., Wei, Q., Boonplueang, R. & Andersen, J. K. (2000). Transgenic mice neuronally expressing baculoviral p35 are resistant to diverse types of induced apoptosis, including seizure-associated neurodegeneration. Proceedings of the National Academy of Sciences, USA 97, 2270-2275.
    179. Vockerodt, M., Haier, B., Buttgereit, P., Tesch, H. & Kube, D. (2001). The Epstein–Barr virus latent membrane protein 1 induces interleukin-10 in Burkitt′s lymphoma cells but not in Hodgkin′s cells involving the p38/SAPK2 pathway. Virology 280, 183-198.
    180. Wang, G. H., Bertin, J., Wang, Y., Martin, D. A., Wang, J., Tomaselli, K. J., Armstrong, R. C. & Cohen, J. I. (1997). Bovine herpesvirus 4 BORFE2 protein inhibits Fas- and tumor necrosis factor receptor 1-induced apoptosis and contains death effector domains shared with other gamma-2 herpesviruses. Journal of Virology 71, 8928-8932.
    181. Wang, X. W., Gibson, M. K., Vermeulen, W., Yeh, H., Forrester, K., Sturzbecher, H. W., Hoeijmakers, J. H. & Harris, C. C. (1995). Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Research 55, 6012-6016.
    182. Wasilenko, S. T., Meyers, A. F., Vander Helm, K. & Barry, M. (2001). Vaccinia virus infection disarms the mitochondrion-mediated pathway of the apoptotic cascade by modulating the permeability transition pore. Journal of Virology 75, 11437-11448.
    183. Webster, K., Parish, J., Pandya, M., Stern, P. L., Clarke, A. R. & Gaston, K. (2000). The human papillomavirus (HPV) 16 E2 protein induces apoptosis in the absence of other HPV proteins and via a p53-dependent pathway. Journal of Biological Chemistry 275, 87-94.
    184. Westendorp, M. O., Shatrov, V. A., Schulze-Osthoff, K., Frank, R., Kraft, M., Los, M., Krammer, P. H., Droge, W. & Lehmann, V. (1995). HIV-1 Tat potentiates TNF-induced NF-κB activation and cytotoxicity by altering the cellular redox state. EMBO Journal 14, 546-554.
    185. White, E., Sabbatini, P., Debbas, M., Wold, W. S., Kusher, D. I. & Gooding, L. R. (1992). The 19-kilodalton adenovirus E1B transforming protein inhibits programmed cell death and prevents cytolysis by tumor necrosis factor α. Molecular and Cellular Biology 12, 2570-2580.
    186. Xu, X., Nash, P. & McFadden, G. (2000). Myxoma virus expresses a TNF receptor homolog with two distinct functions. Virus Genes 21, 97-109.
    187. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T. I., Jones, D. P. & Wang, X. (1997). Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129-1132.
    188. Yew, P. R., Liu, X. & Berk, A. J. (1994). Adenovirus E1B oncoprotein tethers a transcriptional repression domain to p53. Genes & Development 8, 190-202.
    189. Young, L. S., Dawson, C. W. & Eliopoulos, A. G. (1999). Epstein–Barr virus and apoptosis: viral mimicry of cellular pathways. Biochemical Society Transactions 27, 807-812.
    190. Zauli, G., Gibellini, D., Milani, D., Mazzoni, M., Borgatti, P., La Placa, M. & Capitani, S. (1993). Human immunodeficiency virus type 1 Tat protein protects lymphoid, epithelial, and neuronal cell lines from death by apoptosis. Cancer Research 53, 4481-4485.
    191. Zauli, G., Milani, D., Mirandola, P., Mazzoni, M., Secchiero, P., Miscia, S. & Capitani, S. (2001). HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway. FASEB Journal 15, 483-491.
    192. Zhang, W., Ramanathan, C. S., Nadimpalli, R. G., Bhat, A. A., Cox, A. G. & Taylor, E. W. (1999). Selenium-dependent glutathione peroxidase modules encoded by RNA viruses. Biological Trace Element Research 70, 97-116.
    193. Zhao, L., Cox, A. G., Ruzicka, J. A., Bhat, A. A., Zhang, W. & Taylor, E. W. (2000). Molecular modeling and in vitro activity of an HIV-1-encoded glutathione peroxidase. Proceedings of the National Academy of Sciences, USA 97, 6356-6361.
    194. Zhou, Q., Snipas, S., Orth, K., Muzio, M., Dixit, V. M. & Salvesen, G. S. (1997). Target protease specificity of the viral serpin CrmA. Analysis of five caspases. Journal of Biological Chemistry 272, 7797-7800.
    195. Zhou, Q., Krebs, J. F., Snipas, S. J., Price, A., Alnemri, E. S., Tomaselli, K. J. & Salvesen, G. S. (1998). Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry 37, 10757-10765.
    196. Zhu, H., Shen, Y. & Shenk, T. (1995). Human cytomegalovirus IE1 and IE2 proteins block apoptosis. Journal of Virology 69, 7960-7970.
    197. Zhu, N., Khoshnan, A., Schneider, R., Matsumoto, M., Dennert, G., Ware, C. & Lai, M. M. (1998). Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. Journal of Virology 72, 3691-3697.
    198. Zhu, Y., Gelbard, H. A., Roshal, M., Pursell, S., Jamieson, B. D. & Planelles, V. (2001). Comparison of cell cycle arrest, transactivation, and apoptosis induced by the simian immunodeficiency virus SIVagm and human immunodeficiency virus type 1 vpr genes. Journal of Virology 75, 3791-3801.
    199. Zwerschke, W. & Jansen-Durr, P. (2000). Cell transformation by the E7 oncoprotein of human papillomavirus type 16: interactions with nuclear and cytoplasmic target proteins. Advances in Cancer Research 78, 1-29.