Distribution of cytomegalovirus gN variants and associated clinical sequelae in infants

Paradowska, Edyta; Jabłońska, Agnieszka; Studzińska, Mirosława; Suski, Patrycja; Kasztelewicz, Beata; Zawilińska, Barbara; Wiśniewska-Ligier, Małgorzata; Dzierżanowska-Fangrat, Katarzyna; Woźniakowska-Gęsicka, Teresa; Czech‐Kowalska, Justyna; Lipka, B.; Kornacka, Maria; Pawlik, Dorota; Tomasik, Tomasz; Kosz-Vnenchak, Magdalena; Leśnikowski, Zbigniew J.

doi:10.1016/j.jcv.2013.05.024

Cited by 26 publications

(27 citation statements)

References 21 publications

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“…A higher incidence of multiple CMV genotypes in both infants (23.7%) and adults (36.4%) was detected. Genotype analysis in the different genes (or regions) found co‐infections with multiple CMV strains in children [Grosjean et al, ; Ross et al, ; de Vries et al, ; Paradowska et al, ], transplant patients [Görzer et al, ; de Vries et al, ; Lisboa et al, ], and in an immunocompetent hosts [Meyer‐König et al, ; Novak et al, ]. Infections with both gH1 and gH2 genotypes were previously detected in infants with congenital CMV infection [Ross et al, ; Pati et al, ] and in transplant recipients [Zhou et al, ; Görzer et al, ; de Vries et al, ].…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus glycoprotein H genotype distribution and the relationship with hearing loss in children

Paradowska

Jabłońska

Studzińska

et al. 2014

Journal of Medical Virology

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Cytomegalovirus (CMV) is a leading cause of congenital infection and a leading infectious cause of hearing loss in children. The ORF UL75 gene encodes envelope glycoprotein H (gH), which is essential for CMV entry into host cells and the target of the immune response in humans. However, the distribution of gH variants and the relationship between the viral genotype, viral load, and sequelae in children infected with CMV is debated. The UL75 genetic variation of CMV isolates from 42 newborns infected congenitally with CMV and 93 infants with postnatal or unproven congenital CMV infection was analyzed. Genotyping was performed by analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. There were no differences in the distribution of gH genotypes in the children infected congenitally and postnatally. Mixed-genotype infections with both gH1 and gH2 variants were detected in approximately 25% of the examined patients. No relationship between UL75 gene polymorphisms and the symptoms at birth was observed. The results suggest that the infection with gH2 genotype diminishes the risk of hearing loss in children (P = 0.010). In addition, sensorineural hearing loss was associated with CMV gH1 genotype infection in infants (P = 0.032) and a high viral load in urine (P = 0.005). In conclusion, it was found that the gH genotype does not predict clinical sequelae in newborn infants following congenital CMV infection. However, these results suggest that the gH genotype might be associated with hearing loss in children.

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Section: Discussionmentioning

confidence: 99%

Cytomegalovirus glycoprotein H genotype distribution and the relationship with hearing loss in children

Paradowska

Jabłońska

Studzińska

et al. 2014

Journal of Medical Virology

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“…These findings have spiked the interest of clinical virologists in identifying potential correlations between genetic variants and the pathogenic potential of different isolates. Several studies have found some evidence to correlate specific genotypes with disease outcome, investigating polymorphisms in the UL55 (glycoprotein B) (16)(17)(18)(19), UL73 (glycoprotein N) (20)(21)(22), UL75 (glycoprotein H) (23), UL144 (tumor necrosis factor alpha [TNF-␣]-like receptor) (24)(25)(26), and UL146 and UL147 (viral CXCL chemokines) (27,28) genes. Others, however, found no evidence of these relationships (29)(30)(31)(32).…”

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confidence: 99%

High-Throughput Analysis of Human Cytomegalovirus Genome Diversity Highlights the Widespread Occurrence of Gene-Disrupting Mutations and Pervasive Recombination

Sijmons

Thys

Ngwese

et al. 2015

J Virol

151

219

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Human cytomegalovirus is a widespread pathogen of major medical importance. It causes significant morbidity and mortality in immunocompromised individuals, and congenital infections can result in severe disabilities or stillbirth. Development of a vaccine is prioritized, but no candidate is close to release. Although correlations of viral genetic variability with pathogenicity are suspected, knowledge about the strain diversity of the 235-kb genome is still limited. In this study, 96 full-length human cytomegalovirus genomes from clinical isolates were characterized, quadrupling the amount of information available for full-genome analysis. These data provide the first high-resolution map of human cytomegalovirus interhost diversity and evolution. We show that cytomegalovirus is significantly more divergent than all other human herpesviruses and highlight hot spots of diversity in the genome. Importantly, 75% of strains are not genetically intact but contain disruptive mutations in a diverse set of 26 genes, including the immunomodulatory genes UL40 and UL111A. These mutants are independent of culture passage artifacts and circulate in natural populations. Pervasive recombination, which is linked to the widespread occurrence of multiple infections, was found throughout the genome. The recombination density was significantly higher than those of other human herpesviruses and correlated with strain diversity. While the overall effects of strong purifying selection on virus evolution are apparent, evidence of diversifying selection was found in several genes encoding proteins that interact with the host immune system, including UL18, UL40, UL142, and UL147. These residues may present phylogenetic signatures of past and ongoing virus-host interactions. IMPORTANCEHuman cytomegalovirus has the largest genome of all viruses that infect humans. Currently, there is a great interest in establishing associations between genetic variants and strain pathogenicity of this herpesvirus. Since the number of publicly available full-genome sequences is limited, knowledge about strain diversity is highly fragmented and biased toward a small set of loci. Combined with our previous work, we have now contributed 101 complete genome sequences. We have used these data to conduct the first high-resolution analysis of interhost genome diversity, providing an unbiased and comprehensive overview of cytomegalovirus variability. These data are of major value to the development of novel antivirals and a vaccine and to identify potential targets for genotype-phenotype experiments. Furthermore, these data have enabled a thorough study of the evolutionary processes that have shaped cytomegalovirus diversity. Human cytomegalovirus (HCMV), the prototype member of the herpesvirus subfamily Betaherpesvirinae, is a widespread and important pathogen. Seroprevalence in the adult population ranges from 45% to 100% (1). After primary infection, HCMV establishes a lifelong, latent infection in myeloid progenitor cells (2). This virus causes mild to ...

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“…In healthy adults, HCMV infection causes few, if any, symptoms, but infections are often much more severe in immunocompromised patients and congenitally infected infants (2)(3)(4). Many reports have focused on the effects of HCMV strain on the biologic properties of the virus, and each clinical HCMV subtype affects the outcomes of HCMV infections (4)(5)(6). Glycoprotein H (gH) is an important target for neutralizing antibodies, but is also believed to be involved in viral entry into cells, which suggests that gH genetic variants can affect viral pathogenicity and the clinical outcomes of immunocompromised patients (7-9).…”

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confidence: 99%

“…Recently, real-time PCR assays have been used for pathogen detection, such as identifying bacteria and viruses (4,15,16). The purpose of the present research is to develop a real-time PCR-based method to accurately identify HCMV gH genotypes using clinical samples.…”

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confidence: 99%

Rapid and Sensitive Identification of Glycoprotein H Genotypes in Clinical Human Cytomegalovirus Samples

Tao

Zhang

et al. 2015

Jpn J Infect Dis

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SUMMARY: Human cytomegalovirus (HCMV) is a common pathogen that causes persistent infections in immune deficient patients and results in significant morbidity and mortality, particularly among transplant recipients and children. Different HCMV glycoprotein H (gH) genotypes may cause different diseases and affect the severity of these diseases. To develop a sensitive quantitative real-time PCR assay that could rapidly distinguish between two HCMV gH genotypes, primers were designed to target the conserved region of the gH gene. gH1 and gH2 probes were designed to target the two variable regions. Standard HCMV strains (AD169 and TOWNE) and 203 clinical urine samples from HCMV infected children were used for the present study. Based on the primer-probe set used to detect the target gH gene segment of HCMV, our quantitative real-time PCR assay specifically discriminated between HCMV gH1 and gH2 with a detection limit of approximately 10 2 viral copies/ml. Among the 203 clinical urine samples tested, 145 were gH1 positive, 56 were gH2 positive, and 2 were positive for both. Thus, we developed a gH gene-based real time-PCR method that could rapidly, stably, and specifically distinguish between two HCMV gH genotypes. We found HCMV gH1 to be common among children examined in Zhejiang, China.

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Distribution of cytomegalovirus gN variants and associated clinical sequelae in infants

Cited by 26 publications

References 21 publications

Cytomegalovirus glycoprotein H genotype distribution and the relationship with hearing loss in children

Cytomegalovirus glycoprotein H genotype distribution and the relationship with hearing loss in children

High-Throughput Analysis of Human Cytomegalovirus Genome Diversity Highlights the Widespread Occurrence of Gene-Disrupting Mutations and Pervasive Recombination

Rapid and Sensitive Identification of Glycoprotein H Genotypes in Clinical Human Cytomegalovirus Samples

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