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Enveloped RNA virus entry is a conceptually simple stepwise process: A virus attaches to host cells, which leads to viral membrane/cellular membrane fusion and viral genome injection into the cytoplasm. The specifics of and intermediate steps during this entry process are complex and vary widely among viruses. Some of these viruses attach and fuse directly with the plasma membrane, whereas others enter endosomes following attachment and subsequently fuse with endosome membranes. The nature of the host/enveloped RNA virus interactions that lead to virion/cell membrane fusion can also vary. With some viruses, the viral glycoprotein specifically and directly binds with high affinity to a cell surface receptor that mediates the fusion process. At the other end of this spectrum are viruses that use broader, less selective mechanisms for cellular attachment. Two commonly used broad mechanisms employed by enveloped RNA viruses are the binding of virion glycoprotein-associated glycans to glycanbinding proteins such as C-type lectins and the binding of virion lipids such as phosphatidylserine (PS) to PS receptors. These glycoprotein-agnostic attachment factors not only attach virus to the surface of cells, but frequently mediate virion internalization to endosomes. Importantly, they do not mediate membrane fusion. Thus, for viruses that use their glycans and/or lipids as attachment/internalization factors, additional entry steps, such as binding within the endosomal compartment to a cellular receptor that stimulates fusion events, are required for productive infection.

The ability of glycans on virion glycoproteins to enhance attachment has been …