We conclude that CLDN1 and CD81 entry factors act in a cooperative manner in a closely linked step during HCV
entry, consistent with earlier reports on CD81-CLDN1 association.17–19 Taken together, our Palbociclib order findings support a model in which viral attachment and interaction with glycosaminoglycans and SR-BI promote or facilitate viral interaction with CD81-CLDN1 complexes. Because anti-CLDN1 antibodies inhibit envelope glycoprotein E2 and virion binding to permissive cells in the absence of any detectable CLDN1-E2 interactions, it is conceivable that CLDN1 association with CD81 enhances viral glycoprotein associations to the HCV coreceptor complex that are required for virus
internalization. These results define the function of CLDN1 in the HCV entry process and highlight new antiviral strategies targeting E2-CD81-CLDN1 interactions. The development of neutralizing anti-CLDN1 antibodies may provide new therapeutic options for the prevention of HCV infection. Our data clearly demonstrate that CLDN1 is a target for HCV therapeutic intervention that may complement ongoing efforts to block intracellular replication events with inhibitors of the HCV proteases and polymerase.9 The observation that anti-CLDN1 had no effect on HepG2 permeability and TJ integrity (Fig. 2) merits further investigation into the use of anti-CLDN1 antibodies as a therapeutic for HCV infection. The production of antibodies directed against HCV entry factors such as CLDN1 may widen the CHIR-99021 ic50 future preventive and therapeutic strategies for HCV infection and may ultimately be used for the prevention of HCV infection following needle stick injury or during liver transplantation. Further efforts are
underway to produce monoclonal anti-CLDN1 antibodies for that strategy. In conclusion, our results suggest that viral entry requires the formation of a virus-coreceptor complex including HCV E2, CD81, and CLDN1. The functional mapping of Morin Hydrate E2-CD81-CLDN1 association and its impact for HCV entry has important implications for the understanding of the very first steps of HCV infection and the development of novel antiviral strategies targeting viral entry. We thank F. V. Chisari (The Scripps Research Institute, La Jolla, CA) for the gift of Huh7.5.1 cells, T. Wakita (National Institute of Infectious Diseases, Tokyo, Japan), and R. Bartenschlager (University of Heidelberg, Heidelberg, Germany) for providing plasmids for production of recombinant HCV Jc1 and JFH-1 HCVpp; J. Ball (University of Nottingham, Nottingham, U. K.) for providing HCV UKN strains; C. Rice (Rockefeller University, New York City, NY) for providing chimeric CLDN1/7 expression plasmids; P. Bachellier and P.