The quasispecies (extremely heterogeneous) nature of viral RNA genome populations: biological relevance — a review

Domingo, Esteban; Martínez‐Salas, Encarnación; Sánchez‐Madrid, Francisco; Torre, Juan Carlos de la; Portela, Agustı́n; Ortı́n, Juan; López-Galı́ndez, Cecilio; Pérez-Breña, Pilar; Villanueva, Nieves; Nájera, Rafael; VandePol, Scott; Steinhauer, David A.; DePolo, Nicholas J.; Holland, John J.

doi:10.1016/0378-1119(85)90017-4

Cited by 480 publications

(286 citation statements)

References 55 publications

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“…Immunocompetent patients with liver disease can immunologically select for mutational variants with the highest degree of fitness in that particular host. 15,16 Patients with alcoholic liver disease exhibit impaired humoral response against virus specific antigens. We have previously described an altered response to epitopes of the hepatitis C virus that are used to define serotypes.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease

et al. 1999

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Alcohol abuse is described as a major cofactor in the development of hepatitis C (HCV) associated liver disease and may play a role in the outcome of interferon-based treatment interventions. The association between HCV viral heterogeneity and alcohol has not been previously described. This study was designed to evaluate the quasispecies nature of the HCV population in patients with compensated and decompensated alcoholic liver disease, to test the hypothesis that alcoholics have greater complexity than matched nonalcoholic controls. A nonisotopic heteroduplex complexity assay (HCA) was first validated by comparison with results of quasispecies complexity determined by subcloning and sequencing of amplicon products from the E2/NS1 hypervariable coding region (HVR). Subsequently Hepatitis C virus (HCV) infection represents an important comorbidity in patients with alcohol abuse and alcoholic liver disease. Seroprevalence surveys have established that 8% to 45% of this cohort may have concomitant HCV antibodies suggestive of active, ongoing infection. 1 The combination of alcohol and HCV has been epidemiologically associated with increased risk of liver disease injury and progression. [2][3][4] Furthermore, there are limited data that suggest that interferon treatment response is also blunted in these patients. 5 The underlying pathophysiology that explains these differences has not yet been elucidated.Factors that may influence disease progression and treatment outcome include virus characteristics and host response. We have previously studied genotype distribution in patients with alcoholic liver disease and did not discern significant variation from nonalcoholic patients. Using a serologic method to assign genotypes, we did observe an increased percentage of untypeable viral isolates, which may be attributable to an altered immune response against type specific epitopes. 6 This observation raised the possibility that altered immunosurveillance might play a role in impaired viral clearance and might permit the development of a population of closely related variants.HCV is an RNA virus that lacks the ability to perform editing and correction in replication products. Therefore, it is capable of generating multiple mutant forms within an individual patient. These variants have been termed quasispecies. The envelope coding domain contains a hypervariable region that is most likely to show inefficient clearance of emerging quasispecies, though mutant emergence and selection may be seen in other coding domains as well. We hypothesized that quasispecies complexity may be increased in alcoholic patients compared with a nonalcoholic control group based on clinical observations of outcomes and interferon response rates. A rapid semiquantitative methodology to assess quasispecies complexity was developed and validated, and the hypothesis was tested in alcoholic patients and a matched control cohort. PATIENTS AND METHODS PatientsThe study cohort consisted of 20 patients with alcoholic liver disease and concomitant HCV infec...

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Section: Discussionmentioning

confidence: 99%

Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease

et al. 1999

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“…15 The high mutation rate associated with HCV replication results in the generation of swarms of mutants known as viral quasispecies. 16,17 Because the behavior of any particular variant may be influenced by the entire viral population, it has been suggested that the quasispecies, and not individual viral genomes, are the target of selection and random drift. 18,19 Early evolution of the viral quasispecies was shown to predict the clinical outcome of acute hepatitis C. 20,21 Likewise, the long-term viral evolution was shown to correlate with the severity of liver disease.…”

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confidence: 99%

Genetic and catalytic efficiency structure of an HCV protease quasispecies

Franco¹,

Parera²,

Aparicio³

et al. 2007

Hepatology

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The HCV nonstructural protein (NS)3/4A serine protease is not only involved in viral polyprotein processing but also efficiently blocks the retinoic-acid-inducible gen I and Toll-like receptor 3 signaling pathways and contributes to virus persistence by enabling HCV to escape the interferon antiviral response. Therefore, the NS3/4A protease has emerged as an ideal target for the control of the disease and the development of new anti-HCV agents. Here, we analyzed, at a high resolution (approximately 100 individual clones), the HCV NS3 protease gene quasispecies from three infected individuals. Nucleotide heterogeneity of 49%, 84%, and 91% were identified, respectively, which created a dense net that linked different parts of the viral population. Minority variants having mutations involved in the acquisition of resistance to current NS3/4A protease inhibitors (PIs) were also found. A vast diversity of different catalytic efficiencies could be distinguished. Importantly, 67% of the analyzed enzymes displayed a detectable protease activity. Moreover, 35% of the minority individual variants showed similar or better catalytic efficiency than the master (most abundant) enzyme. Nevertheless, and in contrast to minority variants, master enzymes always displayed a high catalytic efficiency when different viral polyprotein cleavage sites were tested. Finally, genetic and catalytic efficiency differences were observed when the 3 quasispecies were compared, suggesting that different selective forces were acting in different infected individuals. Conclusion: The rugged HCV protease quasispecies landscape should be able to react to environmental changes that may threaten its survival. (HEPATOLOGY 2007;45:899-910.)

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“…13,14 HCV is genetically heterogeneous because of low viral RNA polymerase fidelity resulting from lack of proofreading 3Ј-5Ј exonuclease activity within the enzyme. 15,16 Because of high mutation rates, HCV circulates as a population of closely related but nonidentical genomes, referred to as quasispecies. [16][17][18] The N terminus of the E2 protein gene, which is the most variable part of the entire HCV genome, is called hypervariable region 1 (HVR1).…”

Section: H Epatitis C Virus (Hcv) Coinfection Is Commonmentioning

confidence: 99%

“…15,16 Because of high mutation rates, HCV circulates as a population of closely related but nonidentical genomes, referred to as quasispecies. [16][17][18] The N terminus of the E2 protein gene, which is the most variable part of the entire HCV genome, is called hypervariable region 1 (HVR1). 19,20 This region encodes for a prominent B cell epitope and its high mutation rate could be important for viral evasion of the host immune system.…”

Section: H Epatitis C Virus (Hcv) Coinfection Is Commonmentioning

confidence: 99%