Viruses and apoptosis: meddling with mitochondria.

Abstract

Virus infection triggers a complex cascade in which the host’s immune system is deployed in order to prevent virus replication and dissemination. The initiation of a self-destruct apoptotic program in infected somatic cells represents a highly effective innate host response employed for curtailing infection. However, viruses have, in turn, evolved diverse strategies to manipulate the host’s apoptotic response to ensure their continued propagation (O’Brien, 1998; Roulston et al., 1999; Tortorella et al., 2000). The ultimate outcome following infection therefore depends on the balance between competing host and viral influences on the cell death program. Apoptotic signals can be classified as “extrinsic” if triggered by death receptor engagement at the cell surface or “intrinsic” if intracellular sensors are triggered (Fig. 1) (Hengartner, 2000; Kroemer and Reed, 2000). The precise nature of the “danger signals” that allow cells to sense infection and consequently the need to initiate apoptosis are varied (Everett and McFadden, 1999), but the activation of apoptotic cascades appears to be an unavoidable consequence of most infections and often requires the development of viral anti-apoptotic defenses. Extrinsic signals can be initiated by adsorption of viral particles during the entry process at the plasma membrane. Attachment of noninfectious, conformationally intact human immunodeficiency virus (HIV), vaccinia virus, and Herpes simplex virus (HSV) particles to the surface of cells is proapoptotic (Esser et al., 2001; Ramsey-Ewing and Moss, 1998; Zhou et al., 2000). Receptormediated death signaling also appears to be triggered during entry of avian–leukosis–sarcoma virus, which attaches to cells by means of a TNF receptor-related protein, CAR1 (Brojatsch et al., 1996). Engagement of this receptor by the viral envelope proteins is sufficient to