Fig. 1.

Summary of genetically humanized mice supporting HCV uptake. The minimal factors required for HCV uptake in human hepatocytes are CD81, SCARB1, CLDN1, and OCLN, with human CD81 and OCLN constituting the minimal set of human factors for entry into murine hepatocytes. Thus, fully immunocompetent mice can support viral uptake by expressing these factors by adenoviral delivery or by genetic manipulation. The latter approach has been further utilized in two ways, transgenic expression of hCD81 and hOCLN under the controlof an albumin promoter or knockin of humanized CD81 and OCLN where the second extracellular loops of the murine orthologs of these two proteins have been altered to facilitate HCV entry. While all these methods have proven successful, the knockin model best matches the natural tissue expression and physiological levels of CD81 and OCLN, which are expressed only in the liver and at supraphysiological levels in adenovirally transduced or transgenic mice