Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene

Abstract

Little is known about virus-host cell interactions that regulate the lytic potential of viruses during productive replication. Sindbis virus (SV), a single-stranded positive-sense RNA virus in the alphavirus genus (family Togaviridae), results in lytic infection in most vertebrate cell lines, but persistent productive infection in post-mitotic neurons. The cellular oncogene bcl-2, which encodes an inner mitochondrial membrane protein of M(r) 26,000 (ref. 2), blocks programmed cell death (apoptosis) in neurons. We therefore investigated whether SV infection induces programmed cell death in non-neuronal cells, and if so, whether virus-induced programmed cell death can be blocked by transfection with bcl-2. We demonstrate that SV infection of baby hamster kidney (BHK-2), mouse neuroblastoma (N18), and rat prostatic adenocarcinoma (AT-3) cells results in programmed cell death, whereas SV infection of bcl-2-transfected AT-3 cells results in long-term persistent productive infection. Thus cellular bcl-2 oncogene expression plays a role in the establishment of persistent viral infection by blocking virus-induced programmed cell death.

Type I interferons are essential mediators of apoptotic death in virally infected cells

“…Moreover, cell death induced by EMCV was strongly inhibited by expression of the bcl-2 cDNA in wild-type EFs (data not shown). In this regard, Bcl-2-inhibitable apoptosis has been reported to be induced by other viruses, such as Sindbis and influenza (Levine et al 1993;Hinshaw et al 1994). Collectively, these results suggest that apoptosis occurs rather generally as a physiological response to virus infection.…”

Mitochondrial factors with dual roles in death and survival

“…However, there are no viruses known that cause acute de novo infections of S. cerevisiae to directly test this hypothesis. In an alternative model in mammals, virus-induced apoptosis is responsible for the pathogenesis caused by viruses such as HIV and mosquito-borne encephalitis viruses (Levine et al, 1993;Hardwick, 1997;Colo´n-Ramos et al, 2003). Most wild yeast strains are persistently infected with viruses, such as the dsRNA L-A virus and associated satellite dsRNA M viruses (Wickner, 1996).…”

Alternate functions of viral regulators of cell death

“…Although the 'lytic' (productive) replication cycles of many viruses indeed result in cell death, these viruses also trigger cells to commit suicide by activating a pathway of programmed cell death. [1][2][3][4] In multicellular organisms, and in colonies of single-cell species, the activation of cell suicide in response to a virus infection is thought to have arisen during evolution as an effective early defense strategy to prevent the spread of infection. 5,6 This ancient altruistic suicide mechanism of infected cells is a crucial component of the innate host response.…”

“…This is not surprising given that Sindbis virus is transmitted in nature from one avian host to another by mosquitoes, and humans are accidental hosts. 3,[14][15][16] The fact that many viruses encode genes that inhibit the cellular death program strongly supports the concept that virus-activated cellular suicide programs evolved as an effective antiviral strategy to interrupt the virus replication cycle, thereby blocking the spread of infection. E1B proteins of adenovirus and P35 of baculovirus were the earliest viral antiapoptotic genes identified.…”