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Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution.

ABSTRACT: Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children ,2 years of age. Little is known about RSV intra-host genetic diversity over the course of infection or about the immune pressures that drive RSV molecular evolution. We performed whole-genome deep-sequencing on 53 RSV-positive samples (37 RSV subgroup A and 16 RSV subgroup B) collected from the upper airways of hospitalized children in southern Vietnam over two consecutive seasons. RSV A NA1 and RSV B BA9 were the predominant genotypes found in our samples, consistent with other reports on global RSV circulation during the same period. For both RSV A and B, the M gene was the most conserved, confirming its potential as a target for novel therapeutics. The G gene was the most variable and was the only gene under detectable positive selection. Further, positively selected sites inG were found in close proximity to and in some cases overlapped with predicted glycosylation motifs, suggesting that selection on amino acid glycosylation may drive viral genetic diversity. We further identified hotspots and coldspots of intra-host genetic diversity in the RSV genome, some of which may highlight previously unknown regions of functional importance.

SUBMITTER: Do LAH

PROVIDER: S-EPMC4804761 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution.

Do Lien Anh Ha LAH Wilm Andreas A van Doorn H Rogier HR Lam Ha Minh HM Sim Shuzhen S Sukumaran Rashmi R Tran Anh Tuan AT Nguyen Bach Hue BH Tran Thi Thu Loan TTL Tran Quynh Huong QH Vo Quoc Bao QB Dac Nguyen Anh Tran NAT Trinh Hong Nhien HN Nguyen Thi Thanh Hai TTH Binh Bao Tinh Le BTL Le Khanh K Nguyen Minh Tien MT Thai Quang Tung QT Vo Thanh Vu TV Ngo Ngoc Quang Minh NQM Dang Thi Kim Huyen TKH Cao Ngoc Huong NH Tran Thu Van TV Ho Lu Viet LV Farrar Jeremy J de Jong Menno M Chen Swaine S Nagarajan Niranjan N Bryant Juliet E JE Hibberd Martin L ML

The Journal of general virology 20151201 12

Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children ,2 years of age. Little is known about RSV intra-host genetic diversity over the course of infection or about the immune pressures that drive RSV molecular evolution. We performed whole-genome deep-sequencing on 53 RSV-positive samples (37 RSV subgroup A and 16 RSV subgroup B) collected from the upper airways of hospitalized children in southern Vietnam over two consecutive seasons. RSV A ...[more]

PMID: 26407694

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Project description:BackgroundFree-running cardiac and respiratory motion-resolved whole-heart five-dimensional (5D) cardiovascular magnetic resonance (CMR) can reduce scan planning and provide a means of evaluating respiratory-driven changes in clinical parameters of interest. However, respiratory-resolved imaging can be limited by user-defined parameters which create trade-offs between residual artifact and motion blur. In this work, we develop and validate strategies for both correction of intra-bin and compensation of inter-bin respiratory motion to improve the quality of 5D CMR.MethodsEach component of the reconstruction framework was systematically validated and compared to the previously established 5D approach using simulated free-running data (N = 50) and a cohort of 32 patients with congenital heart disease. The impact of intra-bin respiratory motion correction was evaluated in terms of image sharpness while inter-bin respiratory motion compensation was evaluated in terms of reconstruction error, compression of respiratory motion, and image sharpness. The full reconstruction framework (intra-acquisition correction and inter-acquisition compensation of respiratory motion [IIMC] 5D) was evaluated in terms of image sharpness and scoring of image quality by expert reviewers.ResultsIntra-bin motion correction provides significantly (p < 0.001) sharper images for both simulated and patient data. Inter-bin motion compensation results in significant (p < 0.001) lower reconstruction error, lower motion compression, and higher sharpness in both simulated (10/11) and patient (9/11) data. The combined framework resulted in significantly (p < 0.001) sharper IIMC 5D reconstructions (End-expiration (End-Exp): 0.45 ± 0.09, End-inspiration (End-Ins): 0.46 ± 0.10) relative to the previously established 5D implementation (End-Exp: 0.43 ± 0.08, End-Ins: 0.39 ± 0.09). Similarly, image scoring by three expert reviewers was significantly (p < 0.001) higher using IIMC 5D (End-Exp: 3.39 ± 0.44, End-Ins: 3.32 ± 0.45) relative to 5D images (End-Exp: 3.02 ± 0.54, End-Ins: 2.45 ± 0.52).ConclusionThe proposed IIMC reconstruction significantly improves the quality of 5D whole-heart MRI. This may be exploited for higher resolution or abbreviated scanning. Further investigation of the diagnostic impact of this framework and comparison to gold standards is needed to understand its full clinical utility, including exploration of respiratory-driven changes in physiological measurements of interest.

Project description:BackgroundSmall hydrophobic (SH) gene is one of the mostly diverse genomic regions of human respiratory syncytial virus (HRSV). Its coding region constitutes less than 50% of the complete gene length, enabling SH gene to be highly variable and the SH protein highly conserved. In standard HRSV molecular epidemiology studies, solely sequences of the second hypervariable region of the glycoprotein gene (HVR2) are analyzed. To what extent do the strains identical in HVR2 differ elsewhere in genomes is rarely investigated. Our goal was to investigate whether diversity and inter-genotype differences observed for HVR2 are also present in the SH gene.MethodsWe sequenced 198 clinical samples collected within a limited area and time frame. In this HRSV collection, rapid and significant changes in HVR2 occurred.ResultsOver 20% of strains from this pool (containing HRSV genotypes NA1, ON1, GA5, BA9 and BA10) would be incorrectly assumed to be identical to another strain if only the HVR2 region was analysed. The majority of differences found in SH gene were located in the 5' untranslated region (UTR). Seven indels were detected, one was genotype GA5 specific. An in-frame deletion of 9 nucleotides (coding for amino acids 49-51) was observed in one of group A strains. Fifteen different SH protein sequences were detected; 68% of strains possessed the consensus sequence and most of others differed from the consensus in only one amino acid (only 4 strains differed in 2 amino acids). The majority of differing amino acids in group A viruses had the same identity as the corresponding amino acids in group B strains. When analysis was restricted to strains with identical HVR2 nucleotide sequences and differing SH protein sequences, 75% of differences observed in the SH ectodomain were located within region coding for amino acids 49-51.ConclusionsBasing HRSV molecular epidemiology studies solely on HVR2 largely underestimates the complexity of circulating virus populations. In strain identification, broadening of the genomic target sequence to SH gene would provide a more comprehensive insight into viral pool versatility and its evolutionary processes.

Dataset Information

Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution.

Publications

Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution.

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