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Vaccine. 2018 Jun 7;36(24):3460-3467. doi: 10.1016/j.vaccine.2018.04.087. Epub 2018 May 8.

Decreased accumulation of subgenomic RNA in human cells infected with vaccine candidate DEN4Δ30 increases viral susceptibility to type I interferon.

Author information

1
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Building 31, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: jose.bustos@unam.mx.
2
Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA. Electronic address: gregory.d.gromowski.civ@mail.mil.
3
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Building 31, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: konstantin.tsetsarkin@nih.gov.
4
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Building 31, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: cfirestone@niaid.nih.gov.
5
Laboratorio de Biología Molecular e Inmunología de arbovirus, Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Av De Los Barrios 1, Los Reyes Ixtacala, 54090 Tlalnepantla, Mexico. Electronic address: tannya.castro@ired.unam.mx.
6
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Building 31, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: apletnev@niaid.nih.gov.
7
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Superiores del IPN, Av. Instituto Politécnico Nacional 2508, Gustavo A. Madero, San Pedro Zacatenco, 07360 CDMX, Mexico. Electronic address: lcedillo@cinvestav.mx.
8
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Building 31, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: swhitehead@niaid.nih.gov.

Abstract

The NIH has developed live attenuated dengue virus (DENV) vaccine candidates by deletion of 30 nucleotides (Δ30) from the untranslated region of the viral genome. Although this attenuation strategy has proven to be effective in generating safe and immunogenic vaccine strains, the molecular mechanism of attenuation is largely unknown. To examine the mediators of the observed attenuation phenotype, differences in translation efficiency, genome replication, cytotoxicity, and type I interferon susceptibility were compared between wild type parental DENV and DENVΔ30 attenuated vaccine candidates. We observed that decreased accumulation of subgenomic RNA (sfRNA) from the vaccine candidates in infected human cells causes increased type I IFN susceptibility and propose this as one of the of attenuation mechanisms produced by the 3' UTR Δ30 mutation.

KEYWORDS:

Dengue; Innate immunity; Vaccine candidate; sfRNA

PMID:
29752023
DOI:
10.1016/j.vaccine.2018.04.087
[Indexed for MEDLINE]

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