Bystander killing during avian leukosis virus subgroup B infection requires TVBS3 signaling

Cell killing by avian leukosis virus subgroup B (ALV-B) in cultures has been extensively studied, but the molecular basis of this process has not been established. Here we show that superinfection, which has been linked to cell killing by AILV-B, plays no crucial role in cell death induction. Instead, we show that signaling by the ALV-B receptor, TVBS3, a member of the tumor necrosis factor receptor family, is essential for ALV-B-mediated cell death. TVBS3 activated caspase-dependent apoptosis during ALV-B infection. Strikingly, apoptosis induction occurred predominantly in uninfected cells, while ALV-B-infected cells were protected against cell death. This bystander killing phenomenon was reproduced in a virus-free system by cocultivating ALV-B Env-expressing cells with TVBS3-expressing cells. Taken together, our results indicated that ALV-B-mediated apoptosis is triggered by ALV-B Env-TVBS3 interactions.