Genotypic analysis of HCMV polymorphism in congenital infections to predict the impact of HCMV disease severity in newborns/infants

Human Cytomegalovirus (HCMV) is the leading cause of birth defects related to an infectious agent. Prevention and clinical interventions for HCMV disease are limited by the absence of an effective vaccine, as well as resistance to antiviral drugs and therapeutic neutralizing antibodies. Recently, it has been proposed that HCMV disease and pathogenesis may be affected by the genetic diversity of the virus, exceptionally high both within and between hosts. Virus load, replication rate and clinical sequels of the congenitally infected infants may thus result from HCMV genetic polymorphism. Although it is known that HCMV can extensively hijack cellular genes that may contribute to its immune evasion capability and that the virus is polymorphic among hosts, the source of genomic variability and the biological relevance remain unresolved. In this study, we aimed to characterize HCMV clinical isolates obtained from newborn infants diagnosed with congenital or postnatal HCMV infection for the genomic variability of specific genes encoding potential virulence factors or involved in antiviral drug resistance and to identify correlations between viral genotypes, phylogeny, in vitro growth properties and clinical sequels. In vitro analysis of the virions by Focus Expansion Assay (FEA) indicated different patterns of replication, that enabled us to group them into three categories: fast-, intermediate-, and slow-replicating strains. Interestingly, the in vitro replication scores correlate with the patients’ viremia titres at the time of sampling. Moreover, preliminary results obtained from the alignment of the HCMV genome sequences and compared to the reference strain Merlin (NC_006273) revealed that divergent clades can be outlined within the viral population, indicating that heterogeneous viruses exist. This study may contribute to understanding the clinical significance of viral genetic diversity in predicting the impact of virulence factor variability on congenital HCMV disease severity.