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
Source: PubMed


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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    • "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. "
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    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.
    Journal of Medical Virology 08/2014; 86(8). DOI:10.1002/jmv.23968 · 2.35 Impact Factor
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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 [1] [2]. 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 [1] [3] [4]. 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 [5]. "
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    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.
    BioMed Research International 07/2014; 2014:175405. DOI:10.1155/2014/175405 · 1.58 Impact Factor
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    • "Owing to the inherent infidelity of the viral RNA-dependent RNA polymerase, the HCV genome accumulates rapidly mutations during replication, leading to a continuous diversification of the intra-host viral population . As a result, each infected individual contains a diverse population of HCV variants or quasispecies [Duffy et al., 2008; Farci, 2011]. Globally, >185 million people are estimated to be infected with HCV, and $350,000 people die every year from hepatitis Crelated liver diseases [EASL, 1999; Mohd Hanafiah et al., 2013]. "
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    ABSTRACT: Hepatitis C virus (HCV) infection presents an important, but underappreciated public health problem in Africa. In Côte d'Ivoire, very little is known about the molecular dynamics of HCV infection. Plasma samples (n = 608) from pregnant women collected in 1995 from Côte d'Ivoire were analyzed in this study. Only 18 specimens (∼3%) were found to be HCV PCR-positive. Phylogenetic analysis of the HCV NS5b sequences showed that the HCV variants belong to genotype 1 (HCV1) (n = 12, 67%) and genotype 2 (HCV2) (n = 6, 33%), with a maximum genetic diversity among HCV variants in each genotype being 20.7% and 24.0%, respectively. Although all HCV2 variants were genetically distant from each other, six HCV1 variants formed two tight sub-clusters belonging to HCV1a and HCV1b. Analysis of molecular variance (AMOVA) showed that the genetic structure of HCV isolates from West Africa with Côte d'Ivoire included were significantly different from Central African strains (P = 0.0001). Examination of intra-host viral populations using next-generation sequencing of the HCV HVR1 showed a significant variation in intra-host genetic diversity among infected individuals, with some strains composed of sub-populations as distant from each other as viral populations from different hosts. Collectively, the results indicate a complex HCV evolution in Côte d'Ivoire, similar to the rest of West Africa, and suggest a unique HCV epidemic history in the country. J. Med. Virol. 2014. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
    Journal of Medical Virology 05/2014; DOI:10.1002/jmv.23897 · 2.35 Impact Factor
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