Filovirus Entry: A Novelty in the Viral Fusion World

Hunt, Catherine L.; Lennemann, Nicholas J.; Maury, Wendy

Model for filoviral entry. Trimers of filoviral GPs on virions interact with both attachment factors (C-type lectins) and receptors (TIM-1) on the surface of permissive cells. Attachment factors are likely to concentrate virions on cells before receptor engagement and virion internalization by macropinocytosis. Macropinocytosis is enhanced by tyrosine kinase receptors such as TAM family members. Following endosomal acidification, Cathepsins L and B trim the EBOV GP to a smaller form that needs at least one as yet undetermined factor to elicit GP fusion with host endosomal membranes. This smaller form of GP is able to interact with both TIM-1 and the endosomal portion of the NPC1 protein; however, whether GP and TIM-1 interact within endosomes is not known. The energetically unfavorable insertion of the EBOV GP 2 fusion loop into host endosomal membranes (i) is followed by the energetically favorable collapse of EBOV GP into a six-helix bundle (ii) allowing for lipid mixing and hemifusion of host and viral membrane lipids (ii). Finally, the hemifused host and viral membranes resolve and a complete pore is formed (iii) through which the viral genomic complex passes into the cytoplasm, allowing the viral replication cycle to continue.