Hepatitis B virus targets lipid transport pathways to infect hepatocytes

Esser, Knud; Cheng, Xiaoming; Wettengel, Jochen M.; Lucifora, Julie; Hansen-Palmus, Lea; Austen, Katharina; Suarez, Armando A.R.; Heintz, Sarah; Testoni, Barbara; Nebioglu, Firat; Pham, Minh Tu; Yang, Shangqing; Zernecke, Alma; Wohlleber, Dirk; Ringelhan, Marc; Broxtermann, Mathias; Hartmann, Daniel; Hüser, Norbert; Mergner, Julia; Pichlmair, Andreas; Thasler, Wolfgang E.; Heikenwalder, Mathias; Gasteiger, Georg; Blutke, Andreas; Walch, Axel; Knolle, Percy A.; Bartenschlager, Ralf; Protzer, Ulrike     «

Esser, Knud; Cheng, Xiaoming; Wettengel, Jochen M.; Lucifora, Julie; Hansen-Palmus, Lea; Austen, Katharina; Suarez, Armando A.R.; Heintz, Sarah; Testoni, Barbara; Nebioglu, Firat; Pham, Minh Tu; Yang, Shangqing; Zernecke, Alma; Wohlleber, Dirk; Ringelhan, Marc; Broxtermann, Mathias; Hartmann, Daniel; Hüser, Norbert; Mergner, Julia; Pichlmair, Andreas; Thasler, Wolfgang E.; Heikenwalder, Mathias; Gasteiger, Georg; Blutke, Andreas; Walch, Axel; Knolle, Percy A.; Bartenschlager, Ralf; Protzer, Ulri...     »

Background and aims: A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV utilizes a physiological liver-directed pathway that supports specific host-cell targeting in vivo. Methods: We established an ex vivo system of perfused human liver tissue that recapitulates the liver physiology to investigate HBV liver targeting. This model allowed us to investigate virus-host cell interactions in a cellular microenvironment mimicking the in vivo situation. Results: HBV was rapidly sequestered by liver macrophages within one hour after a virus pulse, but was detected in hepatocytes only after 16 hours. We found that HBV associates with lipoproteins. Electron- and immunofluorescence microscopy corroborated a co-localization in recycling endosomes within peripheral and liver macrophages. Importantly, recycling endosomes accumulated HBV and cholesterol, followed by transport of HBV back to the cell surface along the cholesterol efflux pathway. To reach hepatocytes as final target cells, HBV was able to utilise the hepatocyte-directed cholesterol transport machinery of macrophages. Conclusions: Our results propose that HBV by binding to liver targeted lipoproteins and utilizing the reverse cholesterol transport pathway of macrophages hijacks the physiological lipid transport pathways to the liver to most efficiently reach its target organ. This may involve trans-infection of liver macrophages and result in deposition of HBV in the perisinusoidal space from where HBV can bind its receptor on hepatocytes.     «

Background and aims: A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV utilizes a physiological liver-directed pathway that supports specific host-cell targeting in vivo. Methods: We established an ex vivo system of perfused human liver tissue that recapitulates the liver physiology to inves...     »