Distribution of the CMV glycoprotein gH/gL/gO and gH/gL/pUL128/pUL130/pUL131A complex variants and associated clinical manifestations in infants infected congenitally or postnatally

Edyta Paradowska,Teresa Woźniakowska-Gęsicka,Małgorzata Wiśniewska-Ligier,Agnieszka Jabłońska,Katarzyna Dzierżanowska-Fangrat,Mirosława Studzińska,Justyna Czech-Kowalska,Beata Kasztelewicz

doi:10.1038/s41598-019-52906-y

Abstract

Human cytomegalovirus (CMV) is a major cause of morbidity in fetuses following intrauterine infection. The glycoprotein (g) envelope trimeric gH/gL/gO and pentameric gH/gL/pUL128/pUL130/pUL131A complexes are required for CMV entry into fibroblasts and endothelial/epithelial cells, respectively, and both are targets for neutralizing antibodies. The role of sequence variability among viral strains in the outcome of congenital CMV infection is controversial. Variation in the CMV UL75 gene encoding glycoprotein H (gH), the UL115 (gL), the UL74 (gO), and the UL128 locus (UL128L) encoding three structural proteins (pUL128, pUL130, and pUL131A) was determined in 82 newborns with congenital CMV infection and 113 infants with postnatal or unproven congenital CMV infection. Genotyping was performed by sequencing analysis of PCR‐amplified fragments and the PCR-restriction fragment length polymorphism (RFLP) method, and the viral load was measured by quantitative real‐time PCR. The obtained results demonstrated that (1) different CMV variants and mixed CMV infections can be detected in newborns infected congenitally; (2) the gH1 genotype, UL130 variant 6, and UL131A variant 1 were associated with some signs/symptoms within cohort of pediatric patients, mainly consisting of infants with symptomatic CMV infection. The results revealed that pUL130, pUL131A, and gH polymorphisms seemed to be associated with the outcome of CMV infection in infants.

Highlights

Human cytomegalovirus (CMV) is an opportunistic ß-herpesvirus that infects 40% to nearly 100% of the adult population worldwide[1,2]
Nucleotide variations is high in glycoprotein N (gN) and glycoprotein O (gO) genes (40–50%), lower differences exist in glycoprotein B and glycoprotein H (gH) genes (5–10%), while the glycoprotein L gene is highly conserved among clinical strains
The gH/glycoprotein L (gL) dimer exists on the CMV surface as part of a trimeric complex with gO, known as the gCIII complex, or a pentameric complex with the UL128 protein, pUL130 and pUL131A29. gO and pUL128-131A bind to the same site on gH/gL through a disulfide bond with gL-Cys[144]

Summary

Introduction

Human cytomegalovirus (CMV) is an opportunistic ß-herpesvirus that infects 40% to nearly 100% of the adult population worldwide[1,2]. The polymorphisms in the CMV genes encoding envelope glycoproteins, important targets of the host immune response, could potentially be associated with variability in the control of virus infection. Recent studies have revealed findings concerning pentamer structure, location of epitopes for neutralizing antibodies and potential binding sites for cell surface receptors[37]. These data suggest that receptor binding triggers a conformational change in the pentamer, allowing it to interact with gB and initiate the membrane fusion process. A response against pentamer in seronegative pregnant women with primary infection is associated with a lower risk of transmission of the virus to the fetus[54] These findings make the gH/gL/pUL128-131A complex a promising vaccine candidate

Methods

Results

Conclusion