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Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay?

ABSTRACT: Hepatitis C virus (HCV) infection is the main cause of chronic hepatitis, affecting an estimated 150 million people worldwide. Initial exposure to HCV is most often followed by chronic hepatitis, with only a minority of individuals spontaneously clearing the virus. The induction of sustained and broadly directed HCV-specific CD4? and CD8? T cell responses, together with neutralizing antibodies (nAb), and specific genetic polymorphism have been associated with spontaneous resolution of the infection. However, due to its high variability, HCV is able to overwhelm the host immune response through the rapid acquisition of mutations in the epitopes targeted by T cells and neutralizing antibodies. In this context, immune-mediated pressure represents the main force in driving HCV evolution. This review summarizes the data on HCV diversity and the current state of knowledge about the contributions of antibodies, T cells, and host genetic polymorphism in driving HCV evolution in vivo.

SUBMITTER: Lapa D

PROVIDER: S-EPMC6523096 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay?

Lapa Daniele D Garbuglia Anna Rosa AR Capobianchi Maria Rosaria MR Del Porto Paola P

Cells 20190403 4

Hepatitis C virus (HCV) infection is the main cause of chronic hepatitis, affecting an estimated 150 million people worldwide. Initial exposure to HCV is most often followed by chronic hepatitis, with only a minority of individuals spontaneously clearing the virus. The induction of sustained and broadly directed HCV-specific CD4⁺ and CD8⁺ T cell responses, together with neutralizing antibodies (nAb), and specific genetic polymorphism have been associated with spontaneous resolution of the infect ...[more]

PMID: 30987134

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Project description:Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed the NS5B polymerase genetic variability in circulating HCV genotypes/subtypes and its impact on the genetic barrier for the development of resistance to clinically relevant nucleoside inhibitors (NIs)/nonnucleoside inhibitors (NNIs). The study included 1,145 NS5B polymerase sequences retrieved from the Los Alamos HCV database and GenBank. The genetic barrier was calculated for drug resistance emergence. Prevalence and genetic barrier were calculated for 1 major NI and 32 NNI resistance variants (13 major and 19 minor) at 21 total NS5B positions. Docking calculations were used to analyze sofosbuvir affinity toward the diverse HCV genotypes. Overall, NS5B polymerase was moderately conserved among all HCV genotypes, with 313/591 amino acid residues (53.0%) showing ?1% variability and 83/591 residues (14.0%) showing high variability (?25.1%). Nine NNI resistance variants (2 major variants, 414L and 423I; 7 minor variants, 316N, 421V, 445F, 482L, 494A, 499A, and 556G) were found as natural polymorphisms in selected genotypes. In particular, 414L and 423I were found in HCV genotype 4 (HCV-4) (n = 14/38, 36.8%) and in all HCV-5 sequences (n = 17, 100%), respectively. Regardless of HCV genotype, the 282T major NI resistance variant and 10 major NNI resistance variants (316Y, 414L, 423I/T/V, 448H, 486V, 495L, 554D, and 559G) always required a single nucleotide substitution to be generated. Conversely, the other 3 major NNI resistance variants (414T, 419S, and 422K) were associated with a different genetic barrier score development among the six HCV genotypes. Sofosbuvir docking analysis highlighted a better ligand affinity toward HCV-2 than toward HCV-3, in agreement with the experimental observations. The genetic variability among HCV genotypes, particularly with the presence of polymorphisms at NNI resistance positions, could affect their responsiveness to NS5B inhibitors. A pretherapy HCV NS5B sequencing could help to provide patients with the full efficacy of NNI-containing regimens.

Dataset Information

Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay?

Publications

Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay?

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