Competing Death Programs in Poliovirus-Infected Cells: Commitment Switch in the Middle of the Infectious Cycle

Abstract

Productive poliovirus infection of HeLa cells leads to the canonical cytopathic effect (CPE), whereas certain types of abortive infection result in apoptosis. To define the time course of commitment to the different types of poliovirus-induced death, inhibitors of viral replication (guanidine HCl) or translation (cycloheximide) were added at different times postinfection (p.i.). Early in the infection (during the first ϳ2 h p.i.), predominantly proapoptotic viral function was expressed, rendering the cells committed to apoptosis, which developed several hours after viral expression was arrested. In the middle of infection, concomitantly with the onset of fast generation of viral progeny, the implementation of the viral apoptotic program was abruptly interrupted. In particular, activation of an Asp-Glu-Val-Asp (DEVD)-specific caspase(s) occurring in the apoptosis-committed cells was prevented by the ongoing productive infection. Simultaneously, the cells retaining normal or nearly normal morphology became committed to CPE, which eventually developed regardless of whether or not further viral expression was allowed to proceed. The implementation of the poliovirus-induced apoptotic program was suppressed in HeLa cells overexpressing the Bcl-2 protein, indicating that the fate of poliovirusinfected cells depends on the balance of host and viral pro-and antiapoptotic factors.Depending on the conditions, poliovirus infection may trigger two different host cell responses, either the canonical cytopathic effect (CPE) or apoptosis (1, 34). The typical features of poliovirus CPE resulting from productive infection (22) include accumulation of membranous vesicles (3, 11), alterations in the plasma membrane permeability (8), rounding up of the infected cells, distortion and displacement of the nuclei, and condensation of chromatin ("pyknosis"). Some of these alterations appear to be manifestations of "true" cell-damaging effects, whereas others reflect at least in part changes in the cellular infrastructure induced by the virus for its own benefit. Thus, cytoplasmic vesicles contain all the components necessary for replication of the viral genome and in fact are the site of this replication (2, 5, 13). Little is known about the mechanisms underlying development of the CPE, although the involvement of nonstructural proteins encoded in the central region of the viral genome in the cytoplasmic vesiculation is well documented (4, 10, 31).On the other hand, poliovirus infection of HeLa cells under restrictive conditions results in a typical apoptotic response: cell shrinkage, plasma membrane blebbing, a high level of chromatin condensation, degradation of the nuclear DNA into high-molecular-mass and oligonucleosome-sized species followed by fragmentation of the cells into membrane-surrounded "apoptotic bodies" (34). Apoptotic reaction, but not CPE, could be prevented by a specific caspase inhibitor, indicating that the two cellular responses to poliovirus infection are controlled separately (1). Apart from the involvement of act...

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