Gp37 regulates the pathogenesis of avian leukosis virus subgroup J via its C-terminus.

Different from other subgroups of avian leukosis viruses (ALVs), ALV-J is highly pathogenic. It is the main culprit causing myeloid leukemia and hemangioma in chickens. The specialty of env gene of ALV-J with low homology to those of other ALVs is linked to its unique pathogenesis, but the underlying mechanism remains unclear. Previous studies show the env of ALV-J can be grouped into three species based on the tyrosine motifs in the cytoplasmic domain (CTD) of Gp37, i.e., the inhibitory, bi-functional and active groups. To explore whether C-terminus or the tyrosine motifs in the CTD of Gp37 affect the pathogenicity of ALV-J, a set of ALV-J infectious clones containing different C-termini of Gp37 or the mutants at the tyrosine sites were tested in vitro and in vivo Viral growth kinetics did not only indicate ALV-J with active env is the fastest in replication and ALV-J with inhibitory env is the lowest, but also indicate the tyrosine sites essentially affected the replication of ALV-J. Moreover, in vivo studies demonstrated the chickens infected by ALV-J with active or bi-functional env showed higher viremia, cloacal viral shedding and viral tissue load compared with those infected by ALV-J with inhibitory env Notably, the chickens infected by ALV-J with active or bi-functional env showed significant loss of body weight compared with the control chickens. Taken together, these findings reveal the C-terminus of Gp37 plays a vital role in ALV-J pathogenesis, and change from inhibitory env to bi-functional or active env increases the pathogenesis of ALV-J.Importance: ALV-J can cause severe immunosuppression and myeloid leukemia in the infected chickens. However, no vaccine or antiviral drug is available against ALV-J, and the mechanism for ALV-J pathogenesis needs to be elucidated. It is generally believed that the gp85 and LTR of ALV contribute to its pathogenesis. Here, we found C-terminus and the tyrosine motifs (YxxM, ITIM, and ITAM-like) in the CTD of Gp37 of ALV-J could affect the pathogenicity of ALV-J in vitro and in vivo The pathogenicity of ALV-J with Gp37 containing ITIM only was significant weaker than ALV-J with Gp37 containing both YxxM and ITIM and ALV-J with Gp37 containing both YxxM and ITAM-like. This study highlights the vital role of the C-terminus of Gp37 in the pathogenesis of ALV-J, and thus provides a new perspective to elucidate the interaction between ALV-J and host and a molecular basis to develop efficient strategies against ALV-J.