Figure 5
Hypothetical mechanisms for the effects of heparin concentration on HBV entry via a two-step process. Dotted lines separate Fig. 5 into three panels. Upper panel: It is generally believed that HBV entry would undergo a 2-step process (see references in Table 1). In step 1, HBV virions would bind to heparin sulfate proteoglycan (HSPG) on the surface of hepatocytes12,20,25. This initial attachment step is then followed by step 2, where the PreS1 peptide of the L-HBsAg would undergo some kind of conformational change (more exposed), and become more “activated” for binding to a bile salt transporter NTCP on the cell surface, leading to the internalization of HBV25. Middle panel: Heparin and heparan sulfate share similar structures18. To explain the stimulatory effect of heparin at physiological concentration (1–5 μg /ml), we postulate here that once soluble heparin binds to the virion surface, it can also activate the PreS1 domain of L-HBsAg. In this scenario, step 1 is no longer necessary for HBV binding to NTCP, and can be bypassed. There are many heparin-binding protein factors in the serum19. It is possible that some unknown heparin binding factor(s) could play a positive role in this viral entry cascade. For example, complex formation of virions, heparin, and heparin-binding proteins, could facilitate either the conventional step 1-binding to HSPG, or the direct binding to NTCP. Lower panel: At non-physiologically high concentrations of heparin, the surface of HBV virions are fully decorated with excessive amounts of heparin. In this case, virions saturated with negatively-charged heparin cannot bind to negatively charged HSPG. We also speculate here that overly heparinated HBV virions cannot activate the PreS1 domain ligand for the NTCP receptor recognition.
