Animal models to study hepatitis C virus infection

With more than 71 million chronically infected people, the hepatitis C virus (HCV) is a major global health concern. Although new direct acting antivirals have significantly improved the rate of HCV cure, high therapy cost, potential emergence of drug-resistant viral variants, and unavailability of a protective vaccine represent challenges for complete HCV eradication. Relevant animal models are required, and additional development remains necessary, to effectively study HCV biology, virus-host interactions and for the evaluation of new antiviral approaches and prophylactic vaccines. The chimpanzee, the only non-human primate susceptible to experimental HCV infection, has been used extensively to study HCV infection, particularly to analyze the innate and adaptive immune response upon infection. However, financial, practical, and especially ethical constraints have urged the exploration of alternative small animal models. These include different types of transgenic mice, immunodeficient mice of which the liver is engrafted with human hepatocytes (humanized mice) and, more recently, immunocompetent rodents that are susceptible to infection with viruses that are closely related to HCV. In this review, we provide an overview of the currently available animal models that have proven valuable for the study of HCV, and discuss their main benefits and weaknesses

Conduit Processes at the Haukadalur Geyser‐Hosting Hydrothermal Field (Iceland) Revealed by In Situ Temperature and High‐Speed Camera Measurements

Geysers fascinate scientists and visitors for several centuries. However, many driving mechanisms such as heat transfer in the conduit and in the subsurface remain poorly understood. We document for the first time transient temperature variations inside the active Strokkur's and nearby quasi-dormant Great Geysir's conduits, Iceland. While recording temperature inside the conduit, we visually monitored Strokkur's activity at the vent with a high-speed camera, providing a high temporal resolution of the eruptions. Our results reveal heat transfer from a bubble trap to and through the conduit. We propose a model for the eruptive cycle of Strokkur that includes vapor slug rise, eruption, and conduit refill. Each water jet of an eruption is marked by an initial pulse of liquid water and vapor, emitted at a velocity between 5 and 28 m/s and generally followed by a second pulse less than a second later. The timing of eruptions coincides with temperature maxima in the conduit. After the eruption, the conduit is refilled by water falling back in the pool and drained from neighboring groundwater-saturated geological units. This results in a temperature drop, the amplitude of which increases with depth while its period is reduced. This reflects faster heat transfer in the deeper than shallower part of the conduit. The amplitude of temperature drop following an eruption also increases with the eruption order, implying larger heat release by higher-order eruptions. Temperature in the conduit subsequently increases until the next eruption, starting then a new cycle

Geysers, Boiling Groundwater and Tectonics: The 3D Subsurface Resistive Structure of the Haukadalur Hydrothermal Field, Iceland

Geysers are among the most fascinating geological features on Earth. Yet, little is still known about their hydrogeological structure at depth. To shed light on the spatial relationships between the vertical conduits and the aquifers feeding them, we conducted a 3D geoelectrical campaign in the Haukadalur hydrothermal field, Iceland. We deployed 24 Iris Fullwavers across the hydrothermal field and inverted resistivity and chargeability measurements. Additionally, we measured temperature variations inside Strokkur and Great Geysir geysers showing temperature fluctuations pointing out the oscillatory behavior that characterizes the geysering cycle of the geysers. By combining a semi-quantitative temperature distribution of the thermal springs across the hydrothermal field with the inversion of the geoelectrical data, we highlight the control that extensional tectonics have on the distribution of fluids across the hydrothermal field. We also point out the occurrence of a common deep groundwater reservoir feeding the hydrothermal centers. Induced polarization data show that the geysers are fed by sub-vertical water-filled fracture zones. The geysers are found at the margins of highly resistive regions where we speculate boiling groundwater and vapor is found. Our proposed model suggests that local waters feeding the main groundwater reservoir downwell from the nearby region and then convect upwards, phase transitioning into vapor at about 200 m depth. From here, fluids flow toward the surface through pipes cutting a highly pressurized and hot system. This study shows to the best of our knowledge the first full 3D tomographic image of a hydrothermal field hosting geysers

Study of Hepatitis E Virus-4 Infection in Human Liver-Chimeric, Immunodeficient, and Immunocompetent Mice

The hepatitis E virus (HEV) is responsible for 20 million infections worldwide per year. Although, HEV infection is mostly self-limiting, immunocompromised individuals may evolve toward chronicity. The lack of an efficient small animal model has hampered the study of HEV and the discovery of anti-HEV therapies. Furthermore, new HEV strains, infectious to humans, are being discovered. Human liver-chimeric mice have greatly aided in the understanding of HEV, but only two genotypes (HEV-1 and HEV-3) have been studied in this model. Moreover, the immunodeficient nature of this mouse model does not allow full investigation of the virus and all aspects of its interaction with the host. Recent studies have shown the susceptibility of regular and nude Balb/c mice to a HEV-4 strain (KM01). This model should allow the investigation of the interplay between HEV and the adaptive immune system of its host, and potential immune-mediated complications. Here, we assess the susceptibility of human liver-chimeric and non-humanised mice to a different HEV-4 strain (BeSW67HEV4-2008). We report that humanised mice could be readily infected with this isolate, resulting in an infection pattern comparable to HEV-3 infection. Despite these results and in contrast to KM01, non-humanised mice were not susceptible to infection with this viral strain. Further investigation, using other HEV-4 isolates, is needed to conclusively determine HEV-4 tropism and mouse susceptibility

Novel HCV Genotype 4d Infectious Systems and Assessment of Direct-Acting Antivirals and Antibody Neutralization

Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups in Europe. However, 4d infectious culture systems are not available, hampering studies of drugs, as well as neutralizing antibodies relevant for HCV vaccine development. We determined the consensus 4d sequence from a chronic hepatitis C patient by next-generation sequencing, generated a full-length clone thereof (pDH13), and demonstrated that pDH13 RNA-transcripts were viable in the human-liver chimeric mouse model, but not in Huh7.5 cells. However, a JFH1-based DH13 Core-NS5A 4d clone encoding A1671S, T1785V, and D2411G was viable in Huh7.5 cells, with efficient growth after inclusion of 10 additional substitutions [4d(C5A)-13m]. The efficacies of NS3/4A protease- and NS5A- inhibitors against genotypes 4a and 4d were similar, except for ledipasvir, which is less potent against 4d. Compared to 4a, the 4d(C5A)-13m virus was more sensitive to neutralizing monoclonal antibodies AR3A and AR5A, as well as 4a and 4d patient plasma antibodies. In conclusion, we developed the first genotype 4d infectious culture system enabling DAA efficacy testing and antibody neutralization assessment critical to optimization of DAA treatments in the clinic and for vaccine design to combat the HCV epidemic