POTENT INHIBITION OF VIRAL FUSION BY THE LIPOPHOSPHOGLYCAN OF LEISHMANIA-DONOVANI

Lipophosphoglycan (LPG) is an amphiphile produced by Leishmania. Its c hemical structure consists of a hydrophilic flexible polymer of repeat ing PO4-6Gal beta 1-4Man alpha 1 units (on average 16 units) linked vi a a hexasaccharide core to a lyso-1-O-alkyl-PI membrane anchor. In the study of viral fusion we report in this paper, we have introduced LPG into human erythrocyte ghost (HEG) membranes, with the purpose of und erstanding how the LPG-induced surface-structural changes may modulate the interactions between a viral envelope and the HEG membranes. We h ave found that LPG, when incorporated at very low concentrations into intact human erythrocyte membranes, strongly inhibits Sendai virus-ind uced hemolysis. When incorporated into HEGs, it reduces the binding of both Sendai and influenza viruses to HEGs; furthermore, it strongly i nhibits the overall viral fusion to HEGs, being among the most potent known inhibitors. We have also shown that LPG stabilizes the bilayer s tructure of phosphatidylethanolamine against the formation of an inver ted-hexagonal structure. We suggest that LPG may give rise to an effec tive ''steric repulsion'' between the viral and HEG membranes, thereby modulating some specific modes of interaction between viral-target me mbranes in the overall fusion process; LPG may also modulate the bendi ng rigidity and the spontaneous curvature of the HEG membrane in the d irection of making the destabilization and rearrangement of the underl ying lipid bilayer more difficult.