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. 2017 May 23:8:934.
doi: 10.3389/fmicb.2017.00934. eCollection 2017.

Positively Selected Sites at HCMV gB Furin Processing Region and Their Effects in Cleavage Efficiency

Lucas M Stangherlin  1 , Felipe N de Paula  1   2 , Marcelo Y Icimoto  3 , Leonardo G P Ruiz  4 , Maurício L Nogueira  4 , Antônio S K Braz  1 , Luiz Juliano  3 , Maria C C da Silva  1
Affiliations

Positively Selected Sites at HCMV gB Furin Processing Region and Their Effects in Cleavage Efficiency

Lucas M Stangherlin et al. Front Microbiol. .

Abstract

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.

Keywords: furin cleavage; gB genotypes; glycoprotein B; human cytomegalovirus; selective pressure.

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Figures

FIGURE 1
FIGURE 1
Multiple sequence alignment of the 35 unique sequences viewed by amino acids. gB1 to gB4 sequences are grouped (brackets). gB 5, 6, and 7 (dots). gBext_35 corresponds to a Gorilla gorilla cytomegalovirus gB sequence, used as external group to root the phylogenetic tree. Arrow indicates the furin cleavage site. Colors represent amino acids properties as shown in the legend.
FIGURE 2
FIGURE 2
Phylogenetic tree containing the 35 unique sequences. Sequences corresponding genotypes gB1 to gB4 are in different colors as indicated. The blue group contains most of the gB3 and gB6; green group contains all the gB2; red group contains all the gB1 and the gB7. Orange group contains all the gB4. The sequences containing positive selective mutations are pointed by arrows and numbered with the codon (in the alignment) which presented the mutation. The bar indicates the phylogenetic distances in terms of genetic change (bar distance = 0.06). Numbers in each node represent genetic change among branches and are expressed as the number of changes divided by the length of the sequence.
FIGURE 3
FIGURE 3
Furin cleavage site and sites under positive selective pressure. Red residues are positive polar, pink are negative polar, and green are neutral polar residues.
FIGURE 4
FIGURE 4
Bayesian Inference by MrBayes software. The probability of positive selective pressure (y-axis) plot for each site (x-axis). The cut-off of probability was 85%.
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