Polymorphisms of the Cytomegalovirus (CMV)–Encoded Tumor Necrosis Factor–α and β‐Chemokine Receptors in Congenital CMV Disease

Abstract

Some congenital cytomegalovirus (CMV) infections lead to neonatal disease, whereas others have no associated sequelae. To explore a possible role for viral genes as determinants of virulence, portions of the UL144 tumor necrosis factor (TNF)-alpha-like receptor gene, the US28 beta-chemokine receptor gene, and the UL55 envelope glycoprotein B gene from 33 patients with congenital CMV infection were sequenced. Three major UL144 subtypes (A, B, and C) and 2 recombinants (A/C and A/B) were detected. Infection with the least common UL144 subtypes (A, C, A/C, and A/B) was associated with unfavorable disease outcome (P=.04). There was no association between specific subtypes of the US28 and UL55 genes and outcome (P=.864 and P=.765, respectively). Multiple genotypes (implying multiple infections) were detected in tissues from 8 of 10 autopsies. Therefore, polymorphism in the CMV-encoded TNF-alpha-like receptor appears to be associated with congenital CMV disease. Other CMV polymorphisms should be further evaluated for potential relevance to neonatal infection, transplantation, and acquired immunodeficiency syndrome-associated CMV diseases.

Human Cytomegalovirus UL144 Gene Polymorphisms in Congenital Infections

“…UL144 genotyping results. The UL144 gene sequences of the 68 samples studied clustered in five genotypes, as previously described by Arav-Boger et al and Lurain et al (1,14) (Fig. 1).…”

“…The UL144 protein may therefore contribute to the ability of HCMV to escape immune clearance and may potentially affect its virulence. Phylogenetic analysis shows that nucleotide sequences of the UL144 gene cluster in three major groups (1,4,14). The link between the polymorphism of putative virulence genes, such as the UL144 gene, and the outcome of congenital infection has scarcely been studied.…”

“…The link between the polymorphism of putative virulence genes, such as the UL144 gene, and the outcome of congenital infection has scarcely been studied. However, Arav-Boger et al (1) reported an interesting association between UL144 genotypes and the outcome of congenital disease, suggesting that UL144 gene polymorphism may have an impact on the severity of the disease. In order to test this hypothesis, we characterized the UL144 polymorphisms of HCMV strains recovered from the amniotic fluid samples of 38 congenitally infected fetuses and in the blood of 30 infected adults enrolled as a control group.…”

Cytomegalovirus Strain Diversity in Seropositive Women

“…In an earlier report, we documented the occurrence of CMV reinfection between pregnancies in seropositive women, and such reinfection could lead to intrauterine transmission and symptomatic congenital CMV infection (5). Several other studies have also documented CMV infection with multiple virus strains in a variety of population groups, including children attending day care centers, human immunodeficiency virusinfected individuals, allograft recipients, and infants with congenital CMV infection (1,2,10,14). Together, the findings of these studies of different population groups suggest that infections with multiple CMV strains occur frequently.…”

The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

“…Epidemiological studies indicate that specific strains of HCMV preferentially circulate in distinct subpopulations (64), suggesting that UL144 may differentially impact latency and/or host immunity depending upon the specific genetic background of the individual. Notably, conflicting conclusions have been reached when assessing the potential role of UL144 in the outcome of congenital HCMV infection (65)(66)(67)(68)(69), and these studies have been performed with people of differing ethnicities, further suggesting that the impact of UL144 on HCMV pathogenesis may be genetically linked and, as yet, remains unclear.…”