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
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Abstract |
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Introduction |
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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)-
-mediated PCD by the expression of dominantnegative I-
B. 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 p17p24 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.
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Signalling mediators (TNF and Fas) |
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IFN pathway mediators |
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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.
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Bcl-2-related proteins |
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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-
-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
).
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Caspase suppressors |
---|
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
).
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Cell cycle manipulators |
---|
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
).
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Oxidative stress regulators |
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Protein kinases |
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Transcriptional modifiers |
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Endoplasmic reticulum-targeting factor |
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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 ).
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Conclusion |
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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.
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Acknowledgments |
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