AAV-HDV an Attractive Platform for the In Vivo Study of HDV Biology and Mechanism of Disease Pathogenesis

Maestro, Sheila; Gómez-Echarte, Nahia; Camps, Gracián; Usai, Carla; Suárez-Amarán, Lester; Vales, África; Olagüe, Cristina; Aldabe, Rafael; González‐Aseguinolaza, Gloria

doi:10.20944/preprints202103.0411.v1

Cited by 5 publications

(1 citation statement)

References 31 publications

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“…This concept is in keeping with a recent study, in a primate model, showing that severe chronic HDV‐infection is characterized by a limited activation of immune responses, challenging the notion that liver damage is exclusively immune‐mediated and arguing in favour of a direct HDV cytopathic effect 42 . Such cytopathic properties can be directly mediated by the different HDAg isoforms, particularly S‐HDAg, that has been shown to induce the formation of aberrant hepatocytes and apoptotic cells in the absence of T‐cell activation 43 …”

Section: Factors Underlying Hdv Pathogenetic Propertiesmentioning

confidence: 99%

Novel concepts on mechanisms underlying Hepatitis Delta virus persistence and related pathogenesis

Salpini

D’Anna

Piermatteo

et al. 2022

Journal of Viral Hepatitis

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Hepatitis Delta virus is the smallest known human virus, exploiting the HBV surface proteins (HBsAg) for the release of its progeny and de novo entry into hepatocytes. Ever growing evidence have highlighted the existence of multiple mechanisms underlying HDV persistence including integrated HBV‐DNA as a source of HBsAg production and the capability of the HDV genome to propagate through cell proliferation, thus supporting a potential HDV persistence even in the absence of HBV. Chronic HDV‐infection causes the most severe form of viral hepatitis, leading to the development of cirrhosis in 15% of cases within 1–2 years and in 50%–60% of cases within 5–10 years. The rates of hepatocellular carcinoma and hepatic decompensation are also 2–3‐fold higher than for HBV mono‐infection. There is the evidence that persistent viral replication plays a key role in triggering liver injury, suggesting the existence of direct viral cytopathic properties that can modulate, synergistically with immune‐responses, the progression towards end‐stage liver diseases. All these aspects can be further exacerbated by the extraordinary degree of viral genetic variability that can promote HDV evasion from immune responses and has enabled viral differentiation into genotypes and subgenotypes with potential different pathobiological properties. In this light, this review aims at providing comprehensive insights of mechanisms (with a focus on virological factors) underlying HDV persistence and pathogenesis, critical in shaping the clinical outcome of the infection. Dissecting these mechanisms is pivotal to optimize therapeutic strategies aimed at fully counteracting this fascinating and fearsome virus.

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Section: Factors Underlying Hdv Pathogenetic Propertiesmentioning

confidence: 99%

Novel concepts on mechanisms underlying Hepatitis Delta virus persistence and related pathogenesis

Salpini

D’Anna

Piermatteo

et al. 2022

Journal of Viral Hepatitis

View full text Add to dashboard Cite

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Hepatitis Delta Virus and Hepatocellular Carcinoma

Lombardo,

Franzè,

Caminiti

et al. 2024

Pathogens

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The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.

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Topoisomerase Inhibitors Increase Episomal DNA Expression by Inducing the Integration of Episomal DNA in Hepatic Cells

Gómez-Moreno,

San Sebastian,

Moya

et al. 2023

Pharmaceutics

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Gene therapy is a promising strategy to treat and cure most inherited metabolic liver disorders. Viral vectors such as those based on adeno-associated viruses (AAVs) and lentiviruses (LVs) are used as vehicles to deliver functional genes to affected hepatocytes. Adverse events associated with the use of high vector doses have motivated the use of small molecules as adjuvants to reduce the dose. In this study, we showed that a one-hour treatment with topoisomerase inhibitors (camptothecin and etoposide) prior to viral transduction is enough to increase AAV and LV reporter expression in non-dividing hepatic cells in culture. Topoisomerase inhibitors increased both integration-competent (ICLV) and integration-deficient (IDLV) LV-derived expression, with a much stronger increase in the IDLV transduction system. In agreement with that, topoisomerase inhibitors increased viral genome integration in both strains, with a greater impact on the IDLV strain, supporting the idea that topoisomerase inhibitors increased episomal DNA integration, especially when viral integrase activity is abolished. These effects correlated with an increase in the DNA damage response produced by the treatments. Our study highlights the need to monitor DNA damage and undesired integration of viral episomal DNAs into the host genome when studying chemical compounds that increase viral transduction.

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AAV-HDV an Attractive Platform for the In Vivo Study of HDV Biology and Mechanism of Disease Pathogenesis

Cited by 5 publications

References 31 publications

Novel concepts on mechanisms underlying Hepatitis Delta virus persistence and related pathogenesis

Novel concepts on mechanisms underlying Hepatitis Delta virus persistence and related pathogenesis

Hepatitis Delta Virus and Hepatocellular Carcinoma

Topoisomerase Inhibitors Increase Episomal DNA Expression by Inducing the Integration of Episomal DNA in Hepatic Cells

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