Conservation of the conformation and positive charges of hepatitis C virusE2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment

Chronic hepatitis C virus (HCV) infection is a major cause of liver disease . The HCV polyprotein contains a hypervariable region (HVR1) located at the N terminus of the second envelope glycoprotein E2. The strong variability of this 27-amino-acid region is due to its apparent tolerance of amino acid substitutions together with strong selection pressures exerted by anti-HCV immune responses. No specific function has so far been attributed to HVR1. However, its presence at the surface of the viral particle suggests that i t might be involved in viral entry. This would imply that HVR1 is not rando mly variable. We sequenced 460 HVR1 clones isolated at various times from s ix HCV-infected patients receiving alpha interferon therapy (which exerts s trong pressure towards quasispecies genetic evolution) and analyzed their a mino acid sequences together with those of 1,382 nonredundant HVR1 sequence s collected from the EMBL database. We found that (i) despite strong amino acid sequence variability related to strong pressures towards change, the c hemicophysical properties and conformation of HVR1 were highly conserved, a nd (ii) HVR1 is a globally basic stretch, with the basic residues located a t specific sequence positions. This conservation of positively charged resi dues indicates that HVR1 is involved in interactions with negatively charge d molecules such as lipids, proteins, or glycosaminoglycans (GAGs). As with many other viruses, possible interaction with GAGs probably plays a role i n host cell recognition and attachment.