Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo

Background and aim. Research on hepatitis B virus (HBV) infection in vivo h as been limited due to the absence of a suitable animal model. We have deve loped a human-mouse radiation chimera in which normal mice, preconditioned by lethal total body irradiation and radioprotected with SCID mouse bone ma rrow cells, are permissive for engraftment of human hematopoietic cells and solid tissues. This resulting human-mouse model, which comprises three gen etically disparate sources of tissue, is therefore termed Trimera. This stu dy was aimed at assessing the effect of human IL-6 on HBV infection in vivo in Trimera mice. Methods. Trimera mice were transplanted with human liver tissue fragments o r with HepG2-derived cell lines, which had been previously infected ex vivo with HBV in the presence or absence of human interleukin-6 (hlL-6) and in the presence of anti-IL-6-neutralizing antibodies. Results. HBV sequences appeared in the sera of animals in which the liver t issue was incubated with both HBV and hIL-6 prior to transplantation. A sim ilar result was obtained when a human hepatoblastoma cell line (HepG2), exp ressing the hIL-6 receptor, was infected ex vivo with HBV in the presence o f hIL-6 prior to their injection into spleens of Trimera mice. However, whe n liver fragments were infected ex vivo and simultaneously treated with neu tralizing antibodies against hIL-6 or were incubated with HBV prior to tran splantation without hIL-6, the rate of mice positive for HBV DNA in their s era was lower. Human mononuclear cells are also permissive for HBV infectio n in vitro: in the presence of hIL-6 the infection of these cells is enhanc ed; and this infection is suppressed by the chimeric protein named Hyper-IL -6, generated by the fusion of hIL-6 to the soluble hIL-6 receptor (sIL-6R alpha, gp80). Conclusion. hIL-6 facilitates HBV infection in vitro and in vivo. (C) 2000 Academic Press.