Polymorphisms within human cytomegalovirus chemokine (UL146/UL147) and cytokine receptor genes (UL144) are not predictive of sequelae in congenitally infected children

Heo, Jun; Petheram, Susie; Demmler, Gail J.; Murph, Jody R.; Adler, Stuart P.; Bale, James F.; Sparer, Tim E.

doi:10.1016/j.virol.2008.05.002

Cited by 36 publications

(57 citation statements)

References 51 publications

(109 reference statements)

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“…However, the large discrepancy suggests that many of the variants that were identified in these intrahost populations are deleterious and are not passed on. This notion is supported by the apparent stability of genotype sequences in patients (30,(65)(66)(67)(68)(69).…”

Section: Resultsmentioning

confidence: 88%

“…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). Overall, these studies have focused on one or, at best, a few genes at a time, ignoring the influence of other variable regions in the genome.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 88%

mentioning

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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show abstract

“…UL 144) and appear to affect the risk of CMV disease by unknown mechanisms (70,71). UL146 is involved in neutrophil chemoattraction and activation; amino acid sequences differ by up to 60% among isolates without any proven relationship to disease severity (71,72).…”

Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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“…The products of the UL146 and UL147 genes have limited homology to CXC chemokines. The pUL146 protein induces neutrophil chemotaxis and calcium mobilization (11).…”

Section: Introductionmentioning

confidence: 99%