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.
Highlights
Human Cytomegalovirus (HCMV) is a ubiquitous human pathogen, present in 40–100% of the global population
In order to determine the glycoprotein B (gB) genotypes present in clinical strains obtained from Brazil, and to establish their relationship to sequences from different geographical locations, DNA amplification of the gB variable region was performed in blood samples obtained from 22 renal recipients, 2 allogeneic transplant recipients, 1 premature newborn and tumor tissues tissue from 6 glioblastoma patients (Supplementary Table S1)
In addition to the sequences obtained from Brazilian patients, 181 sequences from different groups of patients (HIV positive and transplant recipients) from distinct geographic regions were retrieved from GeneBank
Summary
Human Cytomegalovirus (HCMV) is a ubiquitous human pathogen, present in 40–100% of the global population. Viral replication is controlled by the host immune system and infection is asymptomatic. HCMV-associated pathogenesis, predominantly affects immunocompromised individuals such as transplant recipients and AIDS patients (SoderbergNaucler, 2006; Steininger, 2007), while congenital infection by HCMV is a major cause of birth defects (Gaytant et al, 2002; Cannon, 2009). HCMV strains have polymorphisms in several regions (Pignatelli et al, 2004; Renzette et al, 2011, 2013; Sijmons et al, 2014) and in particular, the envelope glycoproteins are of interest as they are involved in events such as cell attachment and entry, and are important targets of the host immune system (Isaacson et al, 2008; Vanarsdall and Johnson, 2012)
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