Apoptosis is associated with virus-induced human diseases of the central nervous system, heart and liver, and causes substantial morbidity and mortality. Although virus-induced apoptosis is well characterized in individual cells in cell culture, virus-induced apoptosis in vivo and the role of apoptosis in virus-induced disease is not well established. This Review focuses on animal models of virus-induced diseases of the central nervous system, heart and liver that provide insights into the role of apoptosis in pathogenesis, the pathways involved and the potential therapeutic implications.Apoptosis plays an essential part in homeostasis, development and human disease by facilitating the removal of unwanted, damaged or infected cells. However, apoptosis may also have a pathogenic role by contributing to cell death and tissue injury. Apoptotic cell death occurs in a wide range of human viral infections, including infections of the central nervous system (CNS), heart and liver. For example, apoptosis can be detected in the brains of patients with virus-induced CNS disease, including patients with HIV-1-associated dementia 1 , herpes simplex virus (HSV) 2,3 and cytomegalovirus (CMV) 3 encephalitis. Furthermore, apoptotic cells can be observed in the diseased human heart during both active and chronic viral myocarditis 4 , and hepatocyte apoptosis is emerging as an important feature of liver injury in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections [5][6][7][8][9][10] .The morphological and nuclear changes associated with apoptosis are typically caused by the sequential activation of a family of aspartate-specific cysteine proteases called caspases [11][12][13] (BOX 1). Caspase 3, the main executioner caspase, can be activated by the initiator caspase, caspase 8, following activation of cell-surface death receptors in the extrinsic apoptotic pathway (BOX 1 ; FIG. 1). Alternatively, the intrinsic apoptotic pathway can activate caspase 3 following release of pro-apoptotic factors from the mitochondria and activation of the initiator caspase, caspase 9 (BOX 1 ; FIG. 1). In some cell types (type I cells), activation of caspase 8 is sufficient for apoptosis. However, in other cell types (type II cells), apoptosis requires intrinsic apoptotic signalling, which can be activated directly or through extrinsic apoptotic signalling through the caspase 8-dependent cleavage of BCL-2 interacting domain death agonist (BID), a member of the BH3-only B-cell lymphoma protein 2 family (BOX 2 ; FIG. Correspondence to P.C. Penny.Clarke@uchsc.edu.
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NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1). Caspase 3 can also be activated by granzyme B, a serine protease found in cytotoxic T lymphocytes (CTLs) (FIG. 1). Granzyme B can also cleave BID, forming the truncated protein gtBID and resulting in the activation of intrinsic apoptotic signalling 14 . Granzyme B and extrinsic apoptotic signalling constitute the two major components of CTL-induced cell death.
B...