Quasispecies Fitness Partition to Characterize the Molecular Status of a Viral Population. Negative Effect of Early Ribavirin Discontinuation in a Chronically Infected HEV Patient
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Samples
- A technical clone of the SARS-CoV-2 S gene (Twist Synthetic SARS-CoV-2 RNA Control 2 MN908947.3, TWIST Biosciences, South San Francisco, CA, USA) sequenced in 12 amplicons [17]. Commercial Twist Synthetic SARS-CoV-2 RNA controls consist of six non-overlapping 5-Kb fragments generated from in vitro transcription of gene fragments. The synthetic controls were diluted at 1:10 to a concentration of 1 × 105 copies per microliter, PCR-amplified following the Sub-ARTIC v3 protocol [41] using a set of 28 primers (A71 to A84) covering the full S gene, and sequenced on a MiSeq Illumina system [42]. The haplotypes and corresponding frequencies in this analysis included all haplotypes common to both DNA strands after a previous filter at 2 reads. That is, at a minimum of 2 + 2 reads.
- Three HCV amplicons from samples taken from a controlled experiment, in which HCV-infected human hepatoma cells were observed in the presence or absence of RBV, favipiravir, or sofosbuvir [43,44]. Briefly, HCV p0 was the parental viral population obtained by electroporation of a transcript of plasmid Jc1FLAG2(p7-nsGluc2A) (a chimera of J6 and JFH-1, genotype 2a) [45] into Huh-7.5-Lunet cells and amplification in Huh-7.5 cells [46]. HCV p100 resulted from passaging the HCV p0 population 100 times in Huh-7.5 reporter cells [47]. HCV p100 was subsequently passaged 10 additional times in the presence of favipiravir (T-705) (Atomax Chemicals Co., Ltd., Shenzhen, China), RBV (Sigma, Kawasaki, Japan), or sofosbuvir. Drug concentrations were adjusted to produce comparable inhibition of HCV p0 progeny production. The amplicons sequenced covered the following HCV genomic regions: A1, spanning genomic residues 7626 to 7962; A2, residues 7941 to 8257; and A3, residues 8229 to 8653. The haplotypes and corresponding frequencies in this analysis included all haplotypes common to both strands, with no previous abundance filter; that is, a minimum of 1 + 1 reads.
4.2. Processing the Sequencing Data
- Obtain Fastq files with Illumina 2 × 300-bp paired-end reads;
- Recover full amplicon reads with FLASH [48] (min. 20-bp overlap, max. 10% mismatches). The 300-bp reads, when overlapped, result in reads covering complete ~400–500 bp amplicons;
- Remove full reads with 5% or more bases below a Phred score of Q30;
- Demultiplex and trim primers (max three differences accepted);
- Collapse reads (molecules) to haplotypes (amplicon-genomes) and their frequencies. The frequencies were calculated per haplotype of each amplicon;
- In certain cases, remove all haplotypes below a fixed frequency threshold;
- Remove all haplotypes that are not common to both DNA strands.
4.3. Quasispecies Fitness Partitions
- Master: the fraction of molecules belonging to the most frequent haplotype; that is, the one present at the highest percentage (p′1 = p1);
- Emerging: the fraction of molecules present at a frequency > 0.1% and less than the master percentage, belonging to haplotypes that are able to compete with the predominant one and possibly replace it (p′2);
- Low fitness: the fraction of molecules present at frequencies from 1% to 0.1%, belonging to haplotypes that have a low probability of progressing to higher frequencies (p′3);
- Very low fitness: the fraction of molecules present at frequencies < 0.1% belonging to haplotypes with very low fitness and to defective genomes. The likely fate of these molecules individually is degradation, but the fraction is continuously fed with new very low fitness genomes produced by replication errors or by host editing activities (p′4).
4.4. Hill Numbers
- At q = 0, the Hill number is the number of haplotypes;
- at q = 1, it corresponds to the exponential of Shannon entropy;
- at q = 2, it is the inverse of the Simpson index; and
- at q = ∞, it is the inverse of the predominant haplotype.
4.5. Abundance Filter Effect on Haplotype Distribution
4.6. Sample Size Dependence
4.7. Distance between Quasispecies, Quasispecies Dendrograms, and Multidimensional Scale Plots (MDS)
4.8. Software and Statistics
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Master | Emerging | RHL_1_0.1 | RHL_0.1 | |
---|---|---|---|---|
Control | 0.436 (0.0030) | 0.283 (0.0566) | 0.085 (0.0232) | 0.197 (0.0304) |
FPV | 0.184 (0.0541) | 0.298 (0.111) | 0.186 (0.0453) | 0.290 (0.0519) |
RBV | 0.211 (0.0235) | 0.331 (0.0586) | 0.160 (0.0404) | 0.293 (0.0366) |
SOF | 0.680 (0.0403) | 0.081 (0.0577) | 0.064 (0.0142) | 0.158 (0.0348) |
Date (Y-M-D) | Interval (Days) | Days Since Diagnosis | Sample ID | LogVL | Observations |
---|---|---|---|---|---|
2018-05-18 | 0 | 0 | 5.91 | Diagnosis | |
2018-05-23 | 5 | 5 | S01 | 5.87 | |
2018-07-31 | 69 | 74 | S03 | 4.60 | Ribavirin 600 mg |
2018-08-28 | 28 | 102 | S04 | 4.60 | |
2018-10-23 | 56 | 158 | 1.54 | EOT | |
2018-11-20 | 28 | 186 | S06 | 3.04 | Relapse |
2019-01-18 | 59 | 245 | S08 | 5.18 | |
2019-10-02 | 257 | 502 | S10 | 6.43 | Ribavirin 800 mg |
2019-10-30 | 28 | 530 | S12 | 4.62 | |
2019-11-27 | 28 | 558 | S14 | 3.18 | |
2019-12-18 | 21 | 579 | S16 | 2.04 | |
2020-03-18 | 91 | 670 | S17 | 3.04 | Ribavirin 1000 mg |
2020-04-20 | 33 | 703 | S18 | 3.40 | |
2020-05-20 | 30 | 733 | S20 | 3.68 | EOT |
2020-06-17 | 28 | 761 | 4.45 | Relapse | |
2021-06-02 | 350 | 1111 | S24 | 6.28 |
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Gregori, J.; Colomer-Castell, S.; Campos, C.; Ibañez-Lligoña, M.; Garcia-Cehic, D.; Rando-Segura, A.; Adombie, C.M.; Pintó, R.; Guix, S.; Bosch, A.; et al. Quasispecies Fitness Partition to Characterize the Molecular Status of a Viral Population. Negative Effect of Early Ribavirin Discontinuation in a Chronically Infected HEV Patient. Int. J. Mol. Sci. 2022, 23, 14654. https://doi.org/10.3390/ijms232314654
Gregori J, Colomer-Castell S, Campos C, Ibañez-Lligoña M, Garcia-Cehic D, Rando-Segura A, Adombie CM, Pintó R, Guix S, Bosch A, et al. Quasispecies Fitness Partition to Characterize the Molecular Status of a Viral Population. Negative Effect of Early Ribavirin Discontinuation in a Chronically Infected HEV Patient. International Journal of Molecular Sciences. 2022; 23(23):14654. https://doi.org/10.3390/ijms232314654
Chicago/Turabian StyleGregori, Josep, Sergi Colomer-Castell, Carolina Campos, Marta Ibañez-Lligoña, Damir Garcia-Cehic, Ariadna Rando-Segura, Caroline Melanie Adombie, Rosa Pintó, Susanna Guix, Albert Bosch, and et al. 2022. "Quasispecies Fitness Partition to Characterize the Molecular Status of a Viral Population. Negative Effect of Early Ribavirin Discontinuation in a Chronically Infected HEV Patient" International Journal of Molecular Sciences 23, no. 23: 14654. https://doi.org/10.3390/ijms232314654