Key result
Positively selected mutations at HCMV gB codons 461 and 462 alter furin cleavage efficiency, with genotype 2 mutations significantly increasing the processing velocity and affinity compared to reference sequences.
Observational (n=213)
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Mutations under positive selective pressure at the HCMV gB furin cleavage site alter the efficiency of cleavage by furin, suggesting evolutionary adaptation to optimize viral processing.
Human cytomegalovirus is a ubiquitous infectious agent that affects mainly immunosuppressed, fetuses, and newborns. The virus has several polymorphic regions, in particular in the envelope glycoproteins. The UL55 gene encodes the glycoprotein B that has a variable region, containing a furin cleavage site and according to the variability different genotypes are characterized. Here we investigated variability and existence of selective pressure on the UL55 variable region containing the furin cleavage site in 213 clinical sequences from patients worldwide. We showed the occurrence of positive selective pressure on gB codons 461 and 462, near the furin cleavage site. Cleavage analysis of synthesized peptides demonstrated that most mutations confer better cleavage by furin, suggesting that evolution is acting in order to increase the efficiency cleavage and supporting the hypothesis that gB processing is important in the host. We also demonstrated that peptides containing sequences, that characterize genotypes gB2 and 3, are differentially cleaved by furin. Our data demonstrate for the first time that variability in the cleavage site is related to degree of gB processing by furin.
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Stangherlin et al. (2017) conducted an observational in Human Cytomegalovirus (HCMV) infection (n=213). Mutations at gB furin cleavage site (codons 461 and 462) vs. Reference sequences (wild-type) was evaluated on Cleavage efficiency by furin (kcat/km ratio). Positively selected mutations at HCMV gB codons 461 and 462 alter furin cleavage efficiency, with genotype 2 mutations significantly increasing the processing velocity and affinity compared to reference sequences.
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