The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is secreted by hepatocytes as an acute phase protein. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of Xeno, PT or mPT gp70 RNAs in livers in various strains of mice. Our results demonstrated that the expression of different gp70 RNAs was remarkably heterogeneous among mouse strains and that serum gp70 production was regulated by multiple genes in physiological vs. inflammatory conditions. In addition, we observed a contribution of PT and mPT gp70s, in addition of Xeno gp70, to serum gp70. Furthermore, we observed an increased expression of intact mPT env RNA, regulated by the Sgp3 locus, in all lupus-prone mice, as compared with non-autoimmune strains of mice. Finally, we demonstrated that TLR7 played a critical role in the expression of gp70 and in the production of anti-gp70 autoantibodies. These data suggest that lupus-prone mice may possess a unique genetic mechanism responsible for the expression of mPT retroviruses, which could act as a triggering factor through activating TLR7 for the development of autoimmune responses in mice predisposed to SLE.