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Impact of IL28 Genotypes and Modeling the Interactions of HCV Core Protein on Treatment of Hepatitis C

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Abstract

Background

Mutations in the core CVR region of hepatitis C virus (HCV) and polymorphisms of interleukin 28B (IL28B) are associated with progression toward liver disease and in response to therapy. In addition, interactions of the core protein with some cell interactors can be related to HCV liver damage.

Aim

This study aimed to evaluate the effect of core mutations as well as IL28B polymorphism on clinical features, sustained virological response (SVR) in 1a and 3a HCV genotypes amongst Iranian HCV infected patients, and the impact of mutations on core protein properties, antigenic properties, and interactions with HCV inhibitors, using several bioinformatics tools.

Methods

Seventy-nine Iranian patients infected with HCV genotypes 1a and 3a and diagnosed with chronic active hepatitis were examined. Plasma viral RNA was used to amplify and sequence the HCV Core gene; also, HCV viral load, molecular genotyping, and the liver enzymes were determined for all samples. The sequencing results were analyzed by several reliable bioinformatics tools to determine the physicochemical properties, B cell epitopes, post-modification changes, and secondary/tertiary structures; and evaluate the interactions with 4 drugs by docking method.

Result

There were some substitutions in core CVR related to ALT and AST enzymes that can lead to HCV advanced liver disease. The most prevalent mutation for 3a genotypes was a substitution in aa 162 (I to V) while we did not find any mutation in 1a responder group. Polymorphism of the rs8099917 showed that the majority of patients had TG heterozygous and carried CT genotype at the rs12979860. Analysis indicated several phosphorylation sits for core protein as well as two important disulfide bonds. Immunogenic prediction showed that core protein can strongly induce the immune system. Interaction analysis, using the docking method revealed two potential interactors (Vitronectin and SETD2).

Conclusion

Generally, mutations in all core CVR regions in all patients showed a relationship between such substitutions and higher liver enzymes that can result in advanced liver disease progression in HCV infected patients. Furthermore, immunoinformatics analysis determined the possible immunodominant regions to be considered in HCV vaccine designs. Furthermore, no association between SVR and IL28B polymorphism was shown. In silico analysis determined modification sites, structures, B-cell epitopes of core protein and interactions with several interactors can lead to persistent HCV infection in the cell and the progress of liver diseases.

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Acknowledgements

The authors would like to thank personnel of Digestive Disease Research Institute (DDRI) of Shariati Hospital, affiliated with Tehran University of Medical Sciences for excellent work in collecting blood samples.‏ The authors would like to express special thanks to Saeed Ghanbari (Phd student of the department of biostatistics, medical school, Shiraz University of Medical Sciences, Shiraz, Iran) for his statistical assistance. The authors wish to thank Mr. H. Argasi and Dr. Nasrin Shokrpour at the Research Consultation Center (RCC) of Shiraz University of Medical Sciences for his invaluable assistance in editing this manuscript.

Funding

This study was funded by Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences.

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Author notes

  1. Tayebeh Hashempour and Behzad Dehghani have contributed equally to this work.

Authors and Affiliations

  1. Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

    Tayebeh Hashempour, Zahra Musavi & Javad Moayedi

  2. Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran

    Behzad Dehghani & Zahra Hasanshahi

  3. Bacteriology and Virology Department, Shiraz University of Medical Sciences, Shiraz, Iran

    Jamal Sarvari & Seyed Younes Hosseini

  4. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

    Ebrahim Hosseini

  5. Gastroenterology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Maryam Moeini

  6. Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Shahin Merat

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  1. Tayebeh Hashempour
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  2. Behzad Dehghani
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Correspondence to Tayebeh Hashempour.

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Conflict of interest

Author Tayebeh Hashempour declares that she has no conflict of interest. Author Behzad Dehghani declares that he has no conflict of interest. Author Zahra Musavi declares that she has no conflict of interest. Author Javad Moayedi declares that he has no conflict of interest. Author Zahra Hasanshahi declares that she has no conflict of interest. Author Jamal Sarvari declares that he has no conflict of interest. Author Seyed Younes Hosseini declares that he has no conflict of interest. Author Ebrahim Hosseini declares that he has no conflict of interest. Author Maryam Moeini declares that she has no conflict of interest. Author Shahin Merat declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors. The study was approved by the local Ethics Committee of Shiraz University of Medical Sciences (Code: 92-18).

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Hashempour, T., Dehghani, B., Musavi, Z. et al. Impact of IL28 Genotypes and Modeling the Interactions of HCV Core Protein on Treatment of Hepatitis C. Interdiscip Sci Comput Life Sci 12, 424–437 (2020). https://doi.org/10.1007/s12539-020-00382-8

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  • DOI: https://doi.org/10.1007/s12539-020-00382-8

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