New Insights into the HCV Quasispecies and Compartmentalization
Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.Seminars in Liver Disease (Impact Factor: 4.95). 11/2011; 31(4):356-74. DOI: 10.1055/s-0031-1297925
Hepatitis C virus (HCV) is a hepatotropic RNA virus with an extraordinary propensity to persist in the vast majority of infected individuals. During replication, because of the inherent infidelity of the viral RNA polymerase, each progeny RNA genome contains mutations that lead to a continuous diversification of the viral population. Consequently, HCV circulates in vivo as a quasispecies, which is a dynamic distribution of divergent but closely related genomes subjected to a continuous process of genetic variation, competition, and selection. This genomic heterogeneity confers a remarkable advantage to the viral population allowing for a rapid adaptation to a changing environment when the virus is subject to selective constraints exerted by the host, such as antiviral immunity, or external to the host, such as antiviral therapy. The large reservoir of variants provided by the quasispecies represents a great challenge for the control of HCV infection and has important biologic implications for viral persistence, host cell tropism, antiviral drug resistance, and development of an HCV vaccine. This review discusses the molecular mechanisms of HCV genetic variation and the biologic and clinical relevance of the quasispecies nature of HCV.
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- "Although the donor virus is already adapted to the liver , it seems that HCV per se is capable of acquiring fitness and overcoming environmental changes regardless of previous situations . An interesting possibility is that the capacity of the virus to produce a broad - mutant spectrum prevails over the prior adaptation to the cognate liver regarding the prospects of population dominance ( Farci , 2011 ) . "
ABSTRACT: The allocation of liver grafts from HCV-positive donors in HCV-infected liver transplant (LT) recipients leads to infection with two different viral populations. In a previous study, we examined quasispecies dynamics during reinfection by clonal sequencing, which did not allow an accurate characterization of coexistence and competition events. To overcome this limitation, we have used deep sequencing analysis of a fragment of the HCV-NS5B gene in 6 HCV-infected LT recipients that received HCV-infected grafts. Successive expansions and contractions of quasispecies complexity were observed, evolving in all cases towards a more homogeneous population. The population that became dominant was the one displaying the highest mutant spectrum complexity. In four patients, coexistence of minority mutants, derived from the donor or the recipient, were detected. In conclusion, our study shows that during reinfection with a different HCV strain in LT recipients, the viral population with the highest diversity becomes always dominant.
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- "Further compounding the clinical management of HCV, HIV co-infection results in decreased response rates to HCV treatment compared to HCV mono-infection [DiMartino et al., 2001; Perez-Olmeda et al., 2003; Chung et al., 2004]. Previous studies have focused largely on HCV monoinfected individuals and reported a non-random distribution of viral variants in various cell types and tissues (reviewed in [Farci, 2011]). This implies that the requirements for HCV replication are cell typedependent and/or that there are distinct selection pressures acting upon viral variants depending upon their major site(s) of replication. "
ABSTRACT: Viral diversity is an important predictor of hepatitis C virus (HCV) treatment response and may influence viral pathogenesis. HIV influences HCV variability in the plasma; however, limited data on viral variability are available from distinct tissue/cell compartments in patients co-infected with HIV and HCV. Thus, this exploratory study evaluated diversity of the hypervariable region 1 (HVR1) of HCV in the plasma and liver for 14 patients co-infected with HIV and HCV. Median intra-patient genetic distances and entropy values were similar in the plasma and liver compartments. Positive immune selection pressure was observed in the plasma for five individuals and in the liver for three individuals. Statistical evidence supporting viral compartmentalization was found in five individuals. Linear regression identified ALT (P = 0.0104) and AST (P = 0.0130) as predictors of viral compartmentalization. A total of 12 signature amino acids that distinguish liver from plasma E1/HVR1 were identified. One signature amino acid was shared by at least two individuals. These findings suggest that HCV compartmentalization is relatively common among patients co-infected with HIV and HCV. These data also imply that evaluating viral diversity, including drug resistance patterns, in the serum/plasma only may not adequately represent viruses replicating with in the liver and, thus, deserves careful consideration in future studies. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
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- "Hepatitis C virus (HCV) displays significant molecular variability and circulates in the infected host as a heterogenous population referred to as quasispecies  . This dynamic population of closely related but not identical variants could play a significant role in immune evasion, resistance to antiviral therapy, and adaptation to the cells of the immune system   . IRES (internal ribosome entry site) sequence is localized between nucleotide positions 40 and 372 and partly overlaps with both the 5 í® í° untraslated region (5 í® í° UTR) and the open reading frame . "
ABSTRACT: Hepatitis C virus (HCV) highly conserved IRES (internal ribosome entry site) sequence, localized within the 5(')-untranslated region (5(')UTR), may determine viral properties like replication efficiency and cell tropism. The aim of the present study was to characterize newly emerging 5(')UTR variants in serum and peripheral blood mononuclear cells (PBMC) in chronic hepatitis C patients treated with interferon (IFN) and ribavirin and to identify their effect on IRES secondary structures. The study group consisted of 87 patients infected with genotype 1b from whom serum and PBMC samples were collected at 9 time points (before, during, and after treatment). New 5(')UTR variants developed in 9 patients. Out of the overall 14 new variants, 9 (64%) were found in PBMC. HCV variants with decreased thermodynamic stability were identified only in PBMC and C183U mutation was the most common one in this compartment. In conclusion, antiviral treatment may favor emergence of new 5(')UTR variants both in blood and in PBMC compartments. However, variants developing in the latter compartment were predicted to have lower thermodynamic stability of the IRES secondary structures compared to serum strains. C-U change in position 183, which has not been described previously, might indicate viral adaptation to lymphoid cells.
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