In the struggle between virus and host, control over the cell's death machinery is crucial for survival. Viruses are obligatory intracellular parasites and, as such, must modulate apoptotic pathways to control the lifespan of their host in order to complete their replication cycle. Many of the counter-assaults mounted by the immune system incorporate activation of the apoptotic pathway—particularly by members of the tumor necrosis factor cytokine family—as a mechanism to restrict viral replication. Thus, apoptosis serves as a powerful selective pressure for the virus to evade. However, for the host, success is harsh and potentially costly, as apoptosis often contributes to pathogenesis. Here we examine some of the molecular mechanisms by which viruses manipulate the apoptotic machinery to their advantage and how we (as vertebrates) have evolved and learned to cope with viral evasion.
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Green, D.R. Apoptotic pathways: paper wraps stone blunts scissors. Cell 102, 1–4 (2000).
Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001).
Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nature Immunol. 3, 221–227 (2002).
Harvey, M. et al. Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nature Genet. 5, 225–229 (1993).
Kannan, K. et al. DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 20, 2225–2234 (2001).
Miyashita, T. & Reed, J.C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995).
Nakano, K. & Vousden, K.H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683–694 (2001).
Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 (2000).
Wu, G.S. et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genet. 17, 141–143 (1997).
Gross, A., McDonnell, J.M. & Korsmeyer, S.J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999).
Lane, D.P. & Crawford, L.V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263 (1979).
Linzer, D.I. & Levine, A.J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43–52 (1979).
Steegenga, W.T., Riteco, N., Jochemsen, A.G., Fallaux, F.J. & Bos, J.L. The large E1B protein together with the E4orf6 protein target p53 for active degradation in adenovirus infected cells. Oncogene 16, 349–357 (1998).
Querido, E. et al. Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev. 15, 3104–3117 (2001).
Scheffner, M., Werness, B.A., Huibregtse, J.M., Levine, A.J. & Howley, P.M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).
Werness, B.A., Levine, A.J. & Howley, P.M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76–79 (1990).
Wang, X.W. et al. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 55, 6012–6016 (1995).
White, E., Cipriani, R., Sabbatini, P. & Denton, A. Adenovirus E1B 19-kilodalton protein overcomes the cytotoxicity of E1A proteins. J. Virol. 65, 2968–2978 (1991).
White, E. Regulation of apoptosis by adenovirus E1A and E1B oncogenes. Semin. Virol. 8, 505–513 (1998).
Henry, H., Thomas, A., Shen, Y. & White, E. Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. Oncogene 21, 748–760 (2002).
Sundararajan, R. & White, E. E1B 19K blocks Bax oligomerization and tumor necrosis factor α- mediated apoptosis. J. Virol. 75, 7506–7516 (2001).
Henderson, S. et al. 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 90, 8479–8483 (1993).
Marshall, W.L., Datta, R., Hanify, K., Teng, E. & Finberg, R.W. U937 cells overexpressing bcl-xL are resistant to human immunodeficiency virus-1-induced apoptosis and human immunodeficiency virus-1 replication. Virology 256, 1–7 (1999).
Sarid, R., Sato, T., Bohenzky, R.A., Russo, J.J. & Chang, Y. Kaposi's sarcoma-associated herpesvirus encodes a functional bcl-2 homologue. Nature Med. 3, 293–298 (1997).
Cheng, E.H. et al. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc. Natl. Acad. Sci. USA 94, 690–694 (1997).
Gangappa, S., van Dyk, L.F., Jewett, T.J., Speck, S.H. & Virgin, H.W. Identification of the in vivo role of a viral bcl-2. J. Exp. Med. 195, 931–940 (2002).
Goldmacher, V.S. et al. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc. Natl. Acad. Sci. USA 96, 12536–12541 (1999).
Tsukahara, T. et al. Induction of Bcl-xL expression by human T-cell leukemia virus type 1 Tax through NF-κB in apoptosis-resistant T-cell transfectants with Tax. J. Virol. 73, 7981–7987 (1999).
Wolf, D. et al. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad- phosphorylation to induce anti-apoptotic signals. Nature Med. 7, 1217–1224 (2001).
Munger, J. & Roizman, B. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc. Natl. Acad. Sci. USA 98, 10410–10415 (2001).
Earnshaw, W.C., Martins, L.M. & Kaufmann, S.H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383–424 (1999).
Huang, H. et al. The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J. Biol. Chem. 275, 26661–26664 (2000).
Suzuki, Y., Nakabayashi, Y. & Takahashi, R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc. Natl. Acad. Sci. USA 98, 8662–8667 (2001).
Deveraux, Q.L. & Reed, J.C. IAP family proteins–suppressors of apoptosis. Genes Dev. 13, 239–252 (1999).
Hay, B.A. Understanding IAP function and regulation: a view from Drosophila. Cell Death Differ. 7, 1045–1056 (2000).
Clem, R.J. Baculoviruses and apoptosis: the good, the bad, and the ugly. Cell Death Differ. 8, 137–143 (2001).
Shi, Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell 9, 459–470 (2002).
Neilan, J.G. et al. An African swine fever virus gene with similarity to the proto-oncogene bcl-2 and the Epstein-Barr virus gene BHRF1. J. Virol. 67, 4391–4394 (1993).
Miura, M., Friedlander, R.M. & Yuan, J. Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Proc. Natl. Acad. Sci. USA 92, 8318–8322 (1995).
Talley, A.K. et al. Tumor necrosis factor α-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA. Mol. Cell. Biol. 15, 2359–2366 (1995).
Tewari, M. & Dixit, V.M. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J. Biol. Chem. 270, 3255–3260 (1995).
Wallach, D. et al. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17, 331–367 (1999).
Smith, C.A. et al. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 248, 1019–1024 (1990).
Reading, P.C., Khanna, A. & Smith, G.L. Vaccinia virus CrmE encodes a soluble and cell surface tumor necrosis factor receptor that contributes to virus virulence. Virology 292, 285–298 (2002).
Upton, C., Macen, J., Schreiber, M. & McFadden, G. Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence. Virology 184, 370–382 (1991).
Schreiber, M., Sedger, L. & McFadden, G. Distinct domains of M-T2, the myxoma virus tumor necrosis factor (TNF) receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition. J. Virol. 71, 2171–2181 (1997).
Brojatsch, J., Naughton, J., Rolls, M.M., Zingler, K. & Young, J.A. CAR1, a TNFR-related protein, is a cellular receptor for cytopathic avian leukosis-sarcoma viruses and mediates apoptosis. Cell 87, 845–855 (1996).
Benedict, C. et al. Cutting edge: A novel viral TNF receptor superfamily member in virulent strains of human cytomegalovirus. J. Immunol. 126, 6967–6970 (1999).
Raftery, M.J. et al. Herpes simplex virus type 1 infection of activated cytotoxic T cells: Induction of fratricide as a mechanism of viral immune evasion. J. Exp. Med. 190, 1103–1104 (1999).
Raftery, M.J. et al. Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 15, 997–1009 (2001).
Uchida, J. et al. Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286, 300–303 (1999).
Shisler, J., Yang, C., Walter, B., Ware, C. & Gooding, L. The adenovirus E3-10. 4K/14. 5K complex mediates loss of cell surface fas (CD95) and resistance to fas-induced apoptosis. J. Virol. 71, 8299–8306 (1997).
Tollefson, A.E. et al. Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells. Nature 392, 726–730 (1998).
Stewart, A.R., Tollefson, A.E., Krajcsi, P., Yei, S.P. & Wold, W.S. The adenovirus E3 10.4K and 14.5K proteins, which function to prevent cytolysis by tumor necrosis factor and to down-regulate the epidermal growth factor receptor, are localized in the plasma membrane. J. Virol. 69, 172–181 (1995).
Benedict, C.A. et al. Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2. J. Biol. Chem. 276, 3270–3278 (2001).
Piguet, V., Schwartz, O., Le Gall, S. & Trono, D. The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors. Immunol. Rev. 168, 51–63 (1999).
Lama, J. & Ware, C.F. Human immunodeficiency virus type 1 Nef mediates sustained membrane expression of tumor necrosis factor and the related cytokine LIGHT on activated T cells. J. Virol. 74, 9396–9402 (2000).
Overbaugh, J. & Bangham, C.R.M. Selection forces and constraints on retroviral sequence variation. Science 292, 1106–1109 (2001).
Ashkenazi, A. & Dixit, V.M. Apoptosis control by death and decoy receptors. Curr. Opin. Cell. Biol. 11, 255–260 (1999).
Sedger, L.M. et al. IFN-γ mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression. J. Immunol. 163, 920–926 (1999).
Vidalain, P.O. et al. Measles virus induces functional TRAIL production by human dendritic cells. J. Virol. 74, 556–559 (2000).
Kayagaki, N. et al. Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J. Immunol. 163, 1906–1913 (1999).
Fanger, N.A., Maliszewski, C.R., Schooley, K. & Griffith, T.S. Human dendritic cells mediate cellular apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J. Exp. Med. 190, 1155–1164 (1999).
Bertin, J. et al. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc. Natl. Acad. Sci. USA 94, 1172–1176 (1997).
Thome, M. & Tschopp, J. Regulation of lymphocyte proliferation and death by FLIP. Nature Rev. Immunol. 1, 50–58 (2001).
Krueger, A., Schmitz, I., Baumann, S., Krammer, P.H. & Kirchhoff, S. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J. Biol. Chem. 276, 20633–20640 (2001).
Skaletskaya, A. et al. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc. Natl. Acad. Sci. USA 7829–7834 (2001).
Chaudhary, P.M., Jasmin, A., Eby, M.T. & Hood, L. Modulation of the NF-κB pathway by virally encoded death effector domains-containing proteins. Oncogene 18, 5738–5746 (1999).
Guidotti, L.G. & Chisari, F.V. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu. Rev. Immunol. 19, 65–91 (2001).
Darnell, J.E. Jr. Studies of IFN-induced transcriptional activation uncover the Jak-Stat pathway. J. Interferon Cytokine Res. 18, 549–554 (1998).
Tan, S.L. & Katze, M.G. The emerging role of the interferon-induced PKR protein kinase as an apoptotic effector: a new face of death? J. Interferon Cytokine Res. 19, 543–554 (1999).
Castelli, J.C. et al. A study of the interferon antiviral mechanism: apoptosis activation by the 2–5A system. J. Exp. Med. 186, 967–972 (1997).
Meurs, E. et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62, 379–390 (1990).
Chu, W.M. et al. JNK2 and IKKβ are required for activating the innate response to viral infection. Immunity 11, 721–731 (1999).
Jagus, R., Joshi, B. & Barber, G.N. PKR, apoptosis and cancer. Int. J. Biochem. Cell. Biol. 31, 123–138 (1999).
Barber, G.N. Host defense, viruses and apoptosis. Cell Death Differ. 8, 113–126 (2001).
Browne, E.P., Wing, B., Coleman, D. & Shenk, T. Altered cellular mRNA levels in human cytomegalovirus-infected fibroblasts: viral block to the accumulation of antiviral mRNAs. J. Virol. 75, 12319–12330 (2001).
Preston, C.M., Harman, A.N. & Nicholl, M.J. Activation of interferon response factor-3 in human cells infected with herpes simplex virus type 1 or human cytomegalovirus. J. Virol. 75, 8909–8916 (2001).
Benedict, C.A. et al. Lymphotoxins and cytomegalovirus cooperatively induce interferon-β, establishing host-virus détente. Immunity 15, 617–626 (2001).
Tortorella, D., Gewurz, B.E., Furman, M.H., Schust, D.J. & Ploegh, H.L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).
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