Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies

Autoři: Ludmila Perelygina aff001;  Min-hsin Chen aff001;  Suganthi Suppiah aff001;  Adebola Adebayo aff001;  Emily Abernathy aff001;  Morna Dorsey aff002;  Lionel Bercovitch aff003;  Kenneth Paris aff004;  Kevin P. White aff005;  Alfons Krol aff005;  Julie Dhossche aff005;  Ivan Y. Torshin aff006;  Natalie Saini aff007;  Leszek J. Klimczak aff008;  Dmitry A. Gordenin aff007;  Andrey Zharkikh aff009;  Stanley Plotkin aff010;  Kathleen E. Sullivan aff011;  Joseph Icenogle aff001
Působiště autorů: Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America aff001;  Department of Pediatrics, University of California, San Francisco, California, United States of America aff002;  Department of Dermatology, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America aff003;  Division of Allergy and Immunology, Children's Hospital New Orleans, New Orleans, Louisiana, United States of America aff004;  Department of Dermatology, Oregon Health & Science University, Portland, Oregon, United States of America aff005;  Institute of Pharmacoinformatics, Federal Research Center “Computer Science and Control” of Russian Academy of Sciences, Dorodnicyn Computing Center, Moscow, Russian Federation aff006;  Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, United States of America aff007;  Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, United States of America aff008;  Myriad Genetics, Inc., Salt Lake City, Utah, United States of America aff009;  University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff010;  Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America aff011
Vyšlo v časopise: Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008080
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008080


Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10−3 subs/site/year and 8.9 x 10−4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.

Klíčová slova:

Antibodies – Granulomas – MMR vaccine – Substitution mutation – Viral genomics – Viral persistence and latency – Rubella virus – Rubella


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