Evolutionary trends of the first hypervariable region of the hepatitis C virus E2 protein in individuals with differing liver disease severity

Hepatitis C virus (HCV) exists as a complex swarm of genetically related viruses known as a quasispecies. Recent work has shown that quasispecies complexity and evolutionary rates are associated with the outcome of acute infection. Knowledge of how the virus population evolves at different stages of chronic infection is less clear. We have studied rates of evolution of the first hypervariable region (HVR1) of the E2 envelope protein in six individuals with disparate liver disease severity. These data show that virus populations present in individuals with mild non-progressive liver disease evolve in a typical Darwinian fashion, with a consistent accumulation of non-synonymous (amino acid-changing) substitutions. By contrast, the virus population remains relatively static in individuals with severe progressive liver disease. Possible mechanisms for this disparity are discussed.

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In Vivo Study of the HC-TN Strain of Hepatitis C Virus Recovered from a Patient with Fulminant Hepatitis: RNA Transcripts of a Molecular Clone (pHC-TN) Are Infectious in Chimpanzees but Not in Huh7.5 Cells

Journal of Virology ◽

10.1128/jvi.01774-06 ◽

2007 ◽

Vol 81 (13) ◽

pp. 7208-7219 ◽

Cited By ~ 41

Author(s):

Akito Sakai ◽

Shingo Takikawa ◽

Robert Thimme ◽

Jean-Christophe Meunier ◽

Hans Christian Spangenberg ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Disease Severity ◽

Neutralizing Antibodies ◽

Viral Evolution ◽

Acute Infection ◽

Hcv Infection ◽

Rna Transcripts

ABSTRACT Both viral and host factors are thought to influence the pathogenesis of hepatitis C virus (HCV) infection. We studied strain HC-TN (genotype 1a), which caused fulminant hepatic failure in a patient and, subsequently, severe hepatitis in a chimpanzee (CH1422), to analyze the relationship between disease severity, host immune response, viral evolution, and outcome. A second chimpanzee (CH1581) was infected from CH1422 plasma, and a third chimpanzee (CH1579) was infected from RNA transcripts of a consensus cDNA of HC-TN (pHC-TN). RNA transcripts of pHC-TN did not replicate in Huh7.5 cells, which were recently found to be susceptible to infection with another fulminant HCV strain (JFH1). The courses of viremia were similar in the three animals. However, CH1581 and CH1579 developed a less severe acute hepatitis than CH1422. CH1579 and CH1422 resolved the infection, whereas CH1581 became persistently infected. CH1579 and CH1581, despite their differing outcomes, both developed significant intrahepatic cellular immune responses, but not antibodies to the envelope glycoproteins or neutralizing antibodies, during the acute infection. We analyzed the polyprotein sequences of virus recovered at five and nine time points from CH1579 and CH1581, respectively, during the first year of follow-up. High mutation rates and high proportions of nonsynonymous mutations suggested immune pressure and positive selection in both animals. Changes were not selected until after the initial decrease in virus titers and after the development of immune responses and hepatitis. Subsequently, however, mutations emerged repeatedly in both animals. Overall, our results indicate that disease severity and outcome of acute HCV infection depend primarily on the host response.

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Acute Hepatitis C Virus Structural Gene Sequences as Predictors of Persistent Viremia: Hypervariable Region 1 as a Decoy

Journal of Virology ◽

10.1128/jvi.73.4.2938-2946.1999 ◽

1999 ◽

Vol 73 (4) ◽

pp. 2938-2946 ◽

Cited By ~ 137

Author(s):

Stuart C. Ray ◽

Yu-Ming Wang ◽

Oliver Laeyendecker ◽

John R. Ticehurst ◽

Stephen A. Villano ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Selective Pressure ◽

Hypervariable Region ◽

Amino Acid Sequences ◽

Heteroduplex Analysis ◽

Acute Hepatitis C ◽

Hypervariable Region 1 ◽

Persistent Viremia ◽

Quasispecies Complexity

ABSTRACT We hypothesized that hepatitis C virus (HCV) persistence is related to the sequence variability of putative envelope genes. This hypothesis was tested by characterizing quasispecies in specimens collected every six months from a cohort of acutely HCV-infected subjects (mean duration of specimen collection, 72 months after seroconversion). We evaluated 5 individuals who spontaneously cleared viremia and 10 individuals with persistent viremia by cloning 33 1-kb amplicons that spanned E1 and the 5′ half of E2, including hypervariable region 1 (HVR1). To assess the quasispecies complexity and to detect variants for sequencing, the first PCR-positive sample was examined by using a previously described method that combines heteroduplex analysis and analysis of single-stranded conformational polymorphisms. The ratio of nonsynonymous to synonymous substitutions (dN/dS ) within each sample was evaluated as an indicator of relative selective pressure. Amino acid sequences were analyzed for signature patterns, glycosylation signals, and charge. Quasispecies complexity was higher and E1dN/dS ratios (selective pressure) were lower in those with persistent viremia; the association with persistence was strengthened by the presence of a combination of both characteristics. In contrast, a trend toward higher HVR1dN/dS ratios was detected among those with persistent viremia. We did not detect any such association for factors that may affect complexity such as serum HCV RNA concentration. HVR1 had a lower positive charge in subjects with persistent viremia, although no consistent motifs were detected. Our data suggest that HCV persistence is associated with a complex quasispecies and immune response to HVR1.

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The Role of Obstetrician/Gynecologists in the Management of Hepatitis C Virus Infection

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/2008/374517 ◽

2008 ◽

Vol 2008 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Bernard Gonik

Keyword(s):

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Source Of Infection ◽

Health Care Practitioners ◽

Counseling And Testing ◽

Specialist Referral ◽

Hcv Transmission ◽

Progressive Liver Disease

Chronic infection with hepatitis C virus (HCV) is a major cause of liver disease-related death and is also the most frequent indication for liver transplantation in USA. Infected individuals can remain asymptomatic for 20 years or more, but they remain at risk for progressive liver disease. They also represent a potential source of infection for others. For reducing the future disease burden due to HCV, obstetrician/gynecologists and primary health care practitioners should be aware of the factors that promote HCV transmission: how to provide counseling and testing, and when specialist referral is needed.

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