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The work at UPM was supported by grants TIN2017-085727-C4-3-P (DeepBio) from Ministerio de Ciencia, Innovacion y Universidades (MCIU) and PID2019-104903RB-100 (funded by the European Union under the FEDER program). Work at CBMSO was supported by grants SAF2014-52400-R from Ministerio de Economia y Competitividad (MINECO), SAF2017-87846-R and BFU2017-91384-EXP from MCIU, PI18/00210 from Instituto de Salud Carlos III (ISCIII), S2013/ABI-2906 (PLATESA from Comunidad de Madrid/FEDER), and S2018/BAA-4370 (PLATESA2 from Comunidad de Madrid/FEDER). C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (CP14/00121 and CPII19/00001), cofinanced by the European Regional Development Fund (ERDF). CIBERehd (Centro de Investigacion en Red de Enfermedades Hepaticas y Digestivas) is funded by Instituto de Salud Carlos III. Institutional grants from the Fundacion Ramon Areces and Banco Santander to the CBMSO are also acknowledged. The team at CBMSO belongs to the Global Virus Network (GVN). Work at Centro Nacional de Microbiologia (ISCIII) was supported by grants SAF2016-77894-R from MINECO and PI13/02269 from ISCIII. C.G.-C. is supported by predoctoral contract PRE2018-083422 from MCIU. B.M.-G. is supported by predoctoral contract PFIS FI19/00119 from ISCIII, cofinanced by Fondo Social Europeo (FSE). The work at Universidad Complutense Madrid has been supported by research grant CTQ2017-87864-C2-2-P from MINECO.

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A Two-Level, Intramutant Spectrum Haplotype Profile of Hepatitis C Virus Revealed by Self-Organized Maps

Publicado en:Microbiology Spectrum. 9 (3): e01459-21- - 2021-12-01 9(3), DOI: 10.1128/Spectrum.01459-21

Autores: Delgado, Soledad; Perales, Celia; Garcia-Crespo, Carlos; Eugenia Soria, Maria; Gallego, Isabel; Isabel de Avila, Ana; Martinez-Gonzalez, Brenda; Vazquez-Sirvent, Lucia; Lopez-Galindez, Cecilio; Moran, Federico; Domingo, Esteban;

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Resumen

RNA viruses replicate as complex mutant spectra termed viral quasi-species. The frequency of each individual genome in a mutant spectrum depends on its rate of generation and its relative fitness in the replicating population ensemble. The advent of deep sequencing methodologies allows for the first-time quantification of haplotype abundances within mutant spectra. There is no information on the haplotype profile of the resident genomes and how the landscape evolves when a virus replicates in a controlled cell culture environment. Here, we report the construction of intramutant spectrum haplotype landscapes of three amplicons of the NS5A-NS5B coding region of hepatitis C virus (HCV). Two-dimensional (2D) neural networks were constructed for 44 related HCV populations derived from a common clonal ancestor that was passaged up to 210 times in human hepatoma Huh-7.5 cells in the absence of external selective pressures. The haplotype profiles consisted of an extended dense basal platform, from which a lower number of protruding higher peaks emerged. As HCV increased its adaptation to the cells, the number of haplotype peaks within each mutant spectrum expanded, and their distribution shifted in the 2D network. The results show that extensive HCV replication in a monotonous cell culture environment does not limit HCV exploration of sequence space through haplotype peak movements. The landscapes reflect dynamic variation in the intramutant spectrum haplotype profile and may serve as a reference to interpret the modifications produced by external selective pressures or to compare with the landscapes of mutant spectra in complex in vivo environments.IMPORTANCE The study provides for the first time the haplotype profile and its variation in the course of virus adaptation to a cell culture environment in the absence of external selective constraints. The deep sequencing-based self-organized maps document a two- layer haplotype distribution with an ample basal platform and a lower number of protruding peaks. The results suggest an inferred intramutant spectrum fitness landscape structure that offers potential benefits for virus resilience to mutational inputs.

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