Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome.
Abstract: Hepacivirus A (also known as nonprimate hepacivirus and equine hepacivirus) is a hepatotropic virus that can cause both transient and persistent infections in horses. The evolution of intrahost viral populations (quasispecies) has not been studied in detail for hepacivirus A, and its roles in immune evasion and persistence are unknown. To address these knowledge gaps, we first evaluated the envelope gene (E1 and E2) diversity of two different hepacivirus A strains (WSU and CU) in longitudinal blood samples from experimentally infected adult horses, juvenile horses (foals), and foals with severe combined immunodeficiency (SCID). Persistent infection with the WSU strain was associated with significantly greater quasispecies diversity than that observed in horses who spontaneously cleared infection ( = 0.0002) or in SCID foals ( < 0.0001). In contrast, the CU strain was able to persist despite significantly lower ( < 0.0001) and relatively static envelope diversity. These findings indicate that envelope diversity is a poor predictor of hepacivirus A infection outcomes and could be dependent on strain-specific factors. Next, entropy analysis was performed on all E1/E2 genes entered into GenBank. This analysis defined three novel hypervariable regions (HVRs) in E2, at residues 391 to 402 (HVR1), 450 to 461 (HVR2), and 550 to 562 (HVR3). For the experimentally infected horses, entropy analysis focusing on the HVRs demonstrated that these regions were under increased selective pressure during persistent infection. Increased diversity in the HVRs was also temporally associated with seroconversion in some horses, suggesting that these regions may be targets of neutralizing antibody and may play a role in immune evasion. Hepacivirus C (hepatitis C virus) is estimated to infect 150 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. In contrast, its closest relative, hepacivirus A, causes relatively mild disease in horses and is frequently cleared. The relationship between quasispecies evolution and infection outcome has not been explored for hepacivirus A. To address this knowledge gap, we examined envelope gene diversity in horses with resolving and persistent infections. Interestingly, two strain-specific patterns of quasispecies diversity emerged. Persistence of the WSU strain was associated with increased quasispecies diversity and the accumulation of amino acid changes within three novel hypervariable regions following seroconversion. These findings provided evidence that envelope gene mutation is influenced by adaptive immune pressure and may contribute to hepacivirus persistence. However, the CU strain persisted despite relative evolutionary stasis, suggesting that some hepacivirus strains may use alternative mechanisms to persist in the host.
Copyright © 2018 American Society for Microbiology.
Publication Date: 2018-08-29 PubMed ID: 29976666PubMed Central: PMC6146699DOI: 10.1128/JVI.00314-18Google Scholar: Lookup
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Summary
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The study investigates the diversity of Hepacivirus A in horses, revealing differences in the virus’s envelope gene between strains and the potential role of adaptive immunity on infection outcomes.
Research Background and Goals
- The focus of the research is Hepacivirus A, known to cause both temporary and continuous infections in horses. The researchers aim to understand how the evolution of viral populations within a host may help the virus evade the host’s immune system.
- The study’s particular interest is on the envelope gene of Hepacivirus A. The envelope gene codes for proteins that surround the virus particle, playing an important role in how the virus enters and interacts with host cells.
- By exploring the envelope gene’s diversity in different viral strains and in hosts having different immune statuses, the researchers aspire to uncover new insights about what may determine the variation of the envelope gene and the consequences on infection outcomes.
Key Findings
- The researchers studied two strains of Hepacivirus A, WSU and CU, in adult horses, juvenile horses, and immune-compromised foals. They found that persistent infections with the WSU strain had more varied virus populations compared to horses that cleared the infection or immune-compromised foals.
- However, the CU strain was able to continue the infection despite significantly less variation in the envelope gene. This suggests that gene diversity may not be a reliable predictor of infection outcomes and other strain-specific factors may be at work.
- Through an entropy (a measure of randomness or disorder) analysis, the researchers identified three points within the E2 region of the envelope gene (specifically residues 391 to 402, 450 to 461, and 550 to 562) that showed a high degree of variability. The researchers posit that these regions might be constantly mutating to evade the host’s immune response.
- Viral persistence in the WSU strain was connected to an increase in population variability and a build-up of changes within these three identified variable regions.
Implications
- The research provides evidence that changes in the envelope gene, likely due to pressure from the host’s adaptive immune system, contribute to the persistence of Hepacivirus A, especially in the WSU strain.
- However, the understanding of the CU strain’s persistence despite relative evolutionary stagnation is less clear. This finding hints at alternative methods that some strains of Hepacivirus might use to maintain a hold in their hosts.
- Findings in this study contribute to a better understanding of how Hepacivirus A evolves and persists in hosts. Additionally, it provides further insights into Hepacivirus A’s relative, Hepacivirus C, a leading cause of serious liver conditions in humans.
Cite This Article
APA
Ramsay JD, Evanoff R, Mealey RH.
(2018).
Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome.
J Virol, 92(18), e00314-18.
https://doi.org/10.1128/JVI.00314-18 Publication
Researcher Affiliations
- Department of Veterinary Microbiology and Immunology, Washington State University, Pullman, Washington, USA jdr105@wsu.edu.
- Department of Veterinary Microbiology and Immunology, Washington State University, Pullman, Washington, USA.
- Department of Veterinary Microbiology and Immunology, Washington State University, Pullman, Washington, USA.
MeSH Terms
- Adaptive Immunity
- Animals
- Flaviviridae Infections / immunology
- Flaviviridae Infections / veterinary
- Flaviviridae Infections / virology
- Genetic Variation
- Hepacivirus / genetics
- Hepacivirus / immunology
- Hepacivirus / physiology
- Horse Diseases / immunology
- Horse Diseases / virology
- Horses
- Immune Evasion
- Quasispecies / genetics
- Viral Envelope Proteins / genetics
- Viral Envelope Proteins / immunology
Grant Funding
- R21 AI126304 / NIAID NIH HHS
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Citations
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