Cytopathic avian retroviruses and the death receptor TVB

Subgroups B and D ASLV infections cause a generalized cytopathic effect (CPE) in cultured cells. Two correlates of ASLV dependent CPE have been established: the ability to recognize the virus receptor TVB and superinfection. TVB is a tumor necrosis factor receptor (TNFR)-related death receptor providing a compelling model for virus induced CPE and directly linking viral Env-receptor interactions to cell death. However, TVB is also a receptor for the non-cytopathic subgroup E ASLV, leading us to investigate the relationships between virus-induced CPE, virus receptor interactions, and TVB signaling in more detail.;In order to understand the molecular basis for the resistance to viral infection that is associated with a recessive resistance allele of TVB, we have characterized the nature of the defect. We show that resistance to infection by subgroups B, D, and E ASLV is explained by the presence of a single base pair mutation that generates an in frame stop codon that is predicted to lead to the production of a severely truncated protein.;Subgroup E ASLV receptor interaction determinants were examined in a structure-function analysis of TVBS1, a receptor for subgroups B, D, and E ASLV. Rational design, construction, and functional analysis of altered TVB receptor proteins indicated a role for residues Tyr-67, Asn-72, and Arg-73 of TVBS1 in subgroup E virus entry.;The contribution of death domain signaling to ASLV dependent CPE was addressed through the use of a putative dominant-negative version of TVB (TVBDeltaDD) in two cell types. We found that like ASLV-B, a subgroup E ASLV vector can be cytopathic. Virus-induced CPE independent of the death domain of TVB was observed for both viral subgroups and was strongly associated with superinfection. However, in all cases where a TVBDeltaDD receptor was expressed, the level of viral DNA that was obtained was significantly higher than that seen in ASLV-B infection of wild-type cells. Presumably, this difference is due to a delay in the establishment of receptor interference. Taken together, this data shows that superinfection can lead to cell death in the ASLV system although it does not rule out the possibility that the receptor may also be involved.