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Combined genetic variants of human cytomegalovirus envelope glycoproteins as congenital infection markers.

ABSTRACT: Human cytomegalovirus (HCMV) is still considered to be the main viral cause of birth defects and long-term neurological and sensory sequelae following congenital infection. Several Authors sustain a key role of HCMV envelope glycoproteins, such as gB, gN and gO - mainly involved in cell targeting, viral penetration and spread - as putative virulence factors. The genes coding for these glycoproteins possess hypervariable regions, resulting in a number of genetic variants in circulating clinical strains. Considering that the genetic polymorphisms underlying the specific differences between gB, gN and gO genotypes can influence the ability of HCMV to preferentially target specific host cells, it is very likely that they play an important role in defining HCMV infection outcome. In the present study, we analysed HCMV gB, gN and gO gene polymorphisms in viral strains isolated from paediatric patients with congenital or post-natal infection, to investigate whether specific genetic variants may be associated with congenital infection.The restriction fragment polymorphisms of genes coding for HCMV gB (UL55), gN (UL73) and gO (UL74) were investigated by analysing viral DNA extracted from 40 urine samples of as many paediatric patients with congenital or post-natal HCMV infection. Randomly selected samples were subjected to DNA sequencing and phylogenetic analysis. Statistical analysis was performed using Fisher's exact test to assess the significance of single and combined glycoprotein genotypes frequency distribution. Statistical significance was considered at a P <0.05.While gB genomic variants were quite homogeneously represented in both paediatric groups, the gN4 genotype significantly prevailed in congenitally infected children (89.5 %) vs post-natally infected children (47.6 %), with a predominance of the gN4c variant (47.4 %). A similar trend was observed for gO3 (52.6 % vs 19 %). Concerning genotypes association, a statistically significant (P = 0.037) gN4-gO3 combination was found specifically in the congenitally infected group.The results indicate that the gN4 (mostly the gN4c variant) and gO3 combined genotypes could provide useful markers of congenital infection and represent suitable candidate molecules for prophylactic vaccine preparations.

SUBMITTER: Arcangeletti MC

PROVIDER: S-EPMC4662005 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Combined genetic variants of human cytomegalovirus envelope glycoproteins as congenital infection markers.

Arcangeletti Maria-Cristina MC Vasile Simone Rosita R Rodighiero Isabella I De Conto Flora F Medici Maria-Cristina MC Martorana Davide D Chezzi Carlo C Calderaro Adriana A

Virology journal 20151126

<h4>Background</h4>Human cytomegalovirus (HCMV) is still considered to be the main viral cause of birth defects and long-term neurological and sensory sequelae following congenital infection. Several Authors sustain a key role of HCMV envelope glycoproteins, such as gB, gN and gO - mainly involved in cell targeting, viral penetration and spread - as putative virulence factors. The genes coding for these glycoproteins possess hypervariable regions, resulting in a number of genetic variants in cir ...[more]

PMID: 26611326

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Project description:ObjectiveTo develop and internally validate a noninvasive method for the prediction of congenital cytomegalovirus (CMV) infection after primary maternal CMV infection.MethodsWe conducted a secondary analysis of a multicenter randomized placebo-controlled trial of CMV hyperimmune globulin to prevent congenital infection. Women were eligible if they had primary CMV infection, defined as detectable plasma CMV-specific immunoglobulin (Ig)M and CMV-specific IgG with avidity less than 50% before 24 weeks of gestation or IgG seroconversion before 28 weeks, and were carrying a singleton fetus without ultrasonographic findings suggestive of CMV infection. Antibody assays were performed in a single reference laboratory. Congenital infection was defined as CMV detection in amniotic fluid, neonatal urine or saliva, or postmortem tissue. Using backward elimination, we developed logit models for prediction of congenital infection using factors known at randomization. The performance of the model was assessed using leave-one-out cross-validation (a method of internal validation).ResultsOf 399 women enrolled in the trial, 344 (86%) had informative data for this analysis. Congenital infection occurred in 68 pregnancies (20%). The best performing model included government-assisted insurance, IgM index 4.5 or higher, IgG avidity less than 32%, and whether CMV was detectable by polymerase chain reaction in maternal plasma at the time of randomization. Cross-validation showed an average area under the curve of 0.76 (95% CI 0.70-0.82), indicating moderate discriminatory ability. More parsimonious one-, two-, and three-factor models performed significantly less well than the four-factor model. Examples of prediction with the four-factor model: for a woman with government-assisted insurance, avidity less than 32%, IgM index 4.5 or higher, and detectable plasma CMV, probability of congenital infection was 0.69 (95% CI 0.53-0.82); for a woman with private insurance, avidity 32% or greater, IgM index less than 4.5, and undetectable plasma CMV, probability of infection was 0.03 (95% CI 0.02-0.07).ConclusionWe developed models to predict congenital CMV infection in the presence of primary maternal CMV infection and absence of ultrasonographic findings suggestive of congenital infection. These models may be useful for patient counseling and decision making.

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Combined genetic variants of human cytomegalovirus envelope glycoproteins as congenital infection markers.

Publications

Combined genetic variants of human cytomegalovirus envelope glycoproteins as congenital infection markers.

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