Hydrophobic α-Helices 1 and 2 of Herpes Simplex Virus gH Interact with Lipids, and Their Mimetic Peptides Enhance Virus Infection and Fusion

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Abstract
Entry of herpes simplex virus into cells occurs by fusion and requires four glycoproteins. gD serves as the receptor binding glycoprotein. Of the remaining glycoproteins, gH carries structural and functional elements typical of class 1 fusion glycoproteins, in particular α-helix 1 (α-H1), with properties of a candidate fusion peptide, and two heptad repeats. Here, we characterized α-H2 and compared it to α-H1. α-H2 (amino acids 513 to 531) is of lower hydrophobicity than α-H1. Its deletion or mutation decreased virus infection and cell fusion. Its replacement with heterologous fusion peptides did not rescue infection and cell fusion beyond the levels exhibited by the α-H2-deleted gH. This contrasts with α-H1, which cannot be deleted and can be functionally replaced with heterologous fusion peptides (T. Gianni et al., J. Virol. 79: 2931-2940, 2005). Synthetic peptides mimicking α-H1 and α-H2 induced fusion of nude lipid vesicles. Importantly, they increased infection of herpes simplex virus, pseudorabies virus, bovine herpesvirus 1, and vesicular stomatitis virus. The α-H1 mimetic peptide was more effective than the α-H2 peptide. Consistent with the findings that gH carries membrane-interacting segments, a soluble form of gH, but not of gD or gB, partitioned with lipid vesicles. Current findings highlight that α-H2 is an important albeit nonessential region for virus entry and fusion. α-H1 and α-H2 share the ability to target the membrane lipids; they contribute to virus entry and fusion, possibly by destabilizing the membranes. However, α-H2 differs from α-H1 in that it is of lower hydrophobicity and cannot be replaced with heterologous fusion peptides.

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