Avian Sarcoma and Leukosis Virus Cytopathic Effect in the Absence of TVB Death Domain Signaling

Abstract

The cytopathic effect (CPE) seen with some subgroups of avian sarcoma and leukosis virus (ASLV) is associated with viral Env activation of the death-promoting activity of TVB (a tumor necrosis factor receptorrelated receptor that is most closely related to mammalian TNF-related apoptosis-inducing ligand [TRAIL] receptors) and with viral superinfection leading to unintegrated viral DNA (UVD) accumulation, which is presumed to activate a cellular DNA damage response. In this study, we employed cells that express signalingdeficient ASLV receptors to demonstrate that an ASLV CPE can be uncoupled from the death-promoting functions of the TVB receptor. However, these cell-killing events were associated with much higher levels of viral superinfection and DNA accumulation than those seen when the virus used signaling-competent TVB receptors. These findings suggest that a putative cellular DNA damage response that is activated by UVD accumulation might act in concert with the death-signaling pathways activated by Env-TVB interactions to trigger cell death. Such a model is consistent with the well-established synergy that exists between TRAILsignaling pathways and DNA damage responses which is currently being exploited in cancer therapy regimens.A number of retroviruses can cause a cytopathic effect (CPE) that is attributed, at least in part, to a function of the viral envelope glycoprotein (Env) (14,29,30,33). For many retroviruses, the CPE is also associated with massive levels of viral superinfection and/or viral DNA accumulation (13,17,27,36,37,40). Increased levels of viral DNA have been postulated to directly trigger a DNA damage response either before or after the formation of the gapped retroviral DNA integration intermediate in cells that are deficient in the nonhomologous DNA end-joining pathway (10,11,21). However, if viral DNA accumulation is important for stimulating cell death, then its role cannot be universal because human immunodeficiency virus type 1 can cause a CPE in the absence of viral DNA synthesis (5,20).We are studying avian sarcoma and leukosis viruses (ASLVs) to better understand how retroviruses can kill their target cells. Certain subgroups of ASLV are cytopathic (e.g., subgroups B, D, and F). Infection by the cytopathic viral subgroups can lead to the death of up to 30 to 40% of target cells in culture during the acute phase of infection (36, 37). This CPE is associated with viral superinfection and increased levels of viral DNA that are not seen during infection by noncytopathic subgroups of ASLV. The determinants of the ASLV-B surface (SU) Env subunit that are important for triggering the viral CPE are also the same as those required for receptor usage (14), leading to the suggestion that Env-receptor interactions might contribute to the viral CPE. This notion was strengthened when the TVB receptor for cytopathic viral subgroups B and D was identified as a tumor necrosis factor receptor (TNFR)-related death receptor that is most closely related to the mammalian DR4 (TRAIL-R1) and DR5 (TRAIL...

Evolution of Broad Host Range in Retroviruses Leads to Cell Death Mediated by Highly Cytopathic Variants

“…In these experiments, elevated levels of viral DNA are strongly correlated with the observed CPE. This study demonstrates that CPE can result from high levels of infection and DNA accumulation alone but indicate that under normal replicative conditions, the receptor probably plays a role in concert with viral DNA to send coordinated signals leading to apoptosis and death (22). Previously, we have described two groups of variants that expand host range.…”

“…These results have led to the hypothesis that ALV-B kills cells as a result of signals mediated by Env-receptor interaction and that infected cells can kill uninfected cells in a "bystander killing" model (11). In contrast, another report has recently shown that alpharetrovirus cytopathic effects can be triggered in the absence of death receptor signaling (22). Further, a noncytopathic subgroup E SU can send proapoptotic signals in the presence of cycloheximide and subgroup E receptor (6).…”

“…Recently, CPE resulting from alpharetrovirus infection has been shown to occur in the absence of death receptors (22). This effect can be caused by alpharetroviruses of subgroups A, B, and E and has been documented under conditions of high receptor expression and with viruses that grow to very high titers.…”

Expression of Murine Leukemia Virus Envelope Protein Is Sufficient for the Induction of Apoptosis

“…It has been demonstrated for several cytopathic retroviruses that there is a strong correlation between virus superinfection and cell killing (4,12,13,16,17,23,33,35). One of the results of retroviral superinfection is the accumulation of high levels of unintegrated viral DNA in cells, which has been implicated in the induction of cytopathic effects (4,12,13,17,23,33,35).…”

“…One of the results of retroviral superinfection is the accumulation of high levels of unintegrated viral DNA in cells, which has been implicated in the induction of cytopathic effects (4,12,13,17,23,33,35). An additional consequence of superinfection by some pathogenic retroviruses, including MCF13 MLV, is the accumulation of high levels of the envelope precursor glycoprotein (gPr80 env ) in the endoplasmic reticulum (ER), which results in ER stress and apoptosis (7,14,15,19,21,30).…”