TVB Receptors for Cytopathic and Noncytopathic Subgroups of Avian Leukosis Viruses Are Functional Death Receptors

Abstract

The identification of TVB S3 , a cellular receptor for the cytopathic subgroups B and D of avian leukosis virus (ALV-B and ALV-D), as a tumor necrosis factor receptor-related death receptor with a cytoplasmic death domain, provides a compelling argument that viral Env-receptor interactions are linked to cell death (4). However, other TVB proteins have been described that appear to have similar death domains but are cellular receptors for the noncytopathic subgroup E of ALV (ALV-E): TVB T , a turkey subgroup E-specific ALV receptor, and TVB S1 , a chicken receptor for subgroups B, D, and E ALV. To begin to understand the role of TVB receptors in the cytopathic effects associated with infection by specific ALV subgroups, we asked whether binding of a soluble ALV-E surface envelope protein (SU) to its receptor can lead to cell death. Here we report that ALV-E SU-receptor interactions can induce apoptosis in quail or turkey cells. We also show directly that TVB S1 and TVB T are functional death receptors that can trigger cell death by apoptosis via a mechanism involving their cytoplasmic death domains and activation of the caspase pathway. These data demonstrate that ALV-B and ALV-E use functional death receptors to enter cells, and it remains to be determined why only subgroups B and D viral infections lead specifically to cell death. Cytopathic retroviruses have been shown to induce cell death (cytopathic effect [CPE]) upon infection of their target cells. Such viruses include avian leukosis viruses (ALVs), avian reticuloendotheliosis viruses (REVs), avian hemangioma viruses (AHVs), feline leukemia viruses (FeLVs), human and simian immunodeficiency viruses (HIVs, and SIVs), visna viruses, equine infectious anemia viruses, and spumaviruses (12,16,23). We are using ALV as a model system to understand how cytopathic retroviruses kill their target cells. ALVs are divided into different subgroups (designated A through J), and three of these viral subgroups (ALV-B, ALV-D, and ALV-F) induce CPEs upon infection of cultured avian cells (24,25). This CPE is manifested during the acute phase of infection when up to 40% of the target cells are killed (24,25). In addition, the genomic DNA contained within the dying cells is fragmented into nucleosomal ladders (24), suggesting that the cells have undergone apoptosis (8,18).It has been proposed that viral superinfection may lead directly to cell death in this system since the dying cells contain multiple (on average, 300 to 400) copies of unintegrated viral DNA (UVD) (24,25). High levels of UVD are also associated with the CPE induced by other retroviruses including REV, visna virus, HIV type 1 and FeLV (23). However, at least for HIV-1, accumulation of UVD is not required for the viral CPE (3, 10). Thus, the role played by viral superinfection in the CPE induced by different retroviruses remains in question.Viral determinants required for the CPE have been mapped to the Env proteins of ALV-B (7), HIV (5), Cas-Br-MLV (15), AHV (17), and FeLV (6), indicating that viral Env-recept...

Bystander Killing during Avian Leukosis Virus Subgroup B Infection Requires TVB S3 Signaling

“…Signaling-deficient TVB S3 contains a substitution of a highly conserved residue in the cytoplasmic death domain (TVB S3 -F292A). Mutation of this residue inhibits signaling by TVB S3 (6,9), while it has no effect on ALV-B entry. Receptor expression levels were high in cell clones QT6-TVB S3 #24, QT6-TVB S3 -FA211, and QT6-TVB S3 -FA212 and low in QT6-TVB S3 -4 ( Fig.…”

“…TVB S3 signaling is required for ALV-B-mediated cell killing. Since high UVD levels were not toxic to cells, we assessed whether ALV-B-induced cell killing is mediated by signaling by the ALV-B receptor, TVB S3 (6,7,16). To test the involvement of the death receptor TVB S3 in ALV-B-mediated cell killing, we expressed wild-type or signaling-deficient TVB S3 in QT6 cells, which lack endogenous TVB S3 .…”

“…TVB S3 , a member of the tumor necrosis receptor family, triggers apoptosis pathways upon activation in mammalian cells (6,9). To study apoptosis induction during ALV-B infection, we challenged DF-1 cells with noncytopathic ALV-A (ALV-A-GFP) and cytopathic ALV-B (ALV-B-GFP) at an MOI of 1.…”

“…This suggestion is further supported by the fact that the receptor for cytopathic ALV-B, TVB S3 , contains three extracellular cysteine-rich domains, a single transmembrane region, and a putative cytoplasmic "death domain." Transient expression of TVB S3 in mammalian cells activates apoptosis, indicating that TVB S3 is a functional death receptor (6). TVB S3 is also able to activate an NF-B-mediated antagonistic pathway that blocks apoptosis (9).…”

Delineation of the cell-extrinsic apoptosis pathway in the zebrafish

“…In Drosophila, a single TNF ligand (Eiger) and its associated receptor (Wengen) induce apoptosis indirectly, by activating the caspase-9 homolog DRONC through the c-Jun N-terminal kinase (JNK) pathway; Drosophila homologs of caspase-8 (DREDD) and FADD do not appear to play a role in the extrinsic apoptosis pathway. 5,6 DD-containing TNFRs have been reported exclusively in vertebrates, with examples in teleost (below), avian, 7 and mammalian species. 3 However, not all DD-containing TNFRs are dedicated activators of the extrinsic apoptosis pathway.…”