Gp37 Regulates the Pathogenesis of Avian Leukosis Virus Subgroup J via Its C Terminus

Abstract

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 distinctiveness of the <i>env</i> 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 that <i>env</i> 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, bifunctional, and active groups. To explore whether the 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 <i>in vitro</i> and <i>in vivo</i> Viral growth kinetics indicated not only that ALV-J with active <i>env</i> is the fastest in replication and ALV-J with inhibitory <i>env</i> is the lowest but also that the tyrosine sites essentially affected the replication of ALV-J. Moreover, <i>in vivo</i> studies demonstrated that chickens infected by ALV-J with active or bifunctional <i>env</i> showed higher viremia, cloacal viral shedding, and viral tissue load than those infected by ALV-J with inhibitory <i>env</i> Notably, the chickens infected by ALV-J with active or bifunctional <i>env</i> showed significant loss of body weight compared with the control chickens. Taken together, these findings reveal that the C terminus of Gp37 plays a vital role in ALV-J pathogenesis, and change from inhibitory <i>env</i> to bifunctional or active <i>env</i> increases the pathogenesis of ALV-J.<b>IMPORTANCE</b> ALV-J can cause severe immunosuppression and myeloid leukemia in 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 <i>gp85</i> and <i>LTR</i> of ALV contribute to its pathogenesis. Here, we found that the 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 <i>in vitro</i> and <i>in vivo</i> The pathogenicity of ALV-J with Gp37 containing ITIM only was significantly less 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 its host and a molecular basis to develop efficient strategies against ALV-J.