Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-a and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.

Hepatitis C virus (HCV) perturbs the host's lipid metabolism and often results in hepatic steatosis. In nonalcoholic fatty liver disease, the intrahepatic down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical mechanism leading to steatosis and its progression toward fibrosis and hepatocellular carcinoma. However, whether an HCV infection triggers the formation of large lipid droplets through PTEN-dependent mechanisms is unknown. We assessed PTEN expression in the livers of patients infected with HCV genotype 1 or 3 with or without steatosis. The role of PTEN in the HCV-induced biogenesis of lipid droplets was further investigated in vitro with hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression was down-regulated at the posttranscriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, down-regulated PTEN expression by a mechanism involving a microRNA-dependent blockade of PTEN messenger RNA translation. PTEN down-regulation promoted in turn a reduction of insulin receptor substrate 1 (IRS1) expression. Interestingly, either PTEN or IRS1 overexpression prevented the development of large lipid droplets, and this indicates that the down-regulation of both PTEN and IRS1 is required to affect the biogenesis of lipid droplets. However, IRS1 knockdown per se did not alter the morphology of lipid droplets, and this suggests that other PTEN-dependent mechanisms are involved in this process. Conclusion: The down-regulation of PTEN and IRS1 is a critical event leading to the HCV genotype 3a-induced formation of large lipid droplets in hepatocytes. (HEPATOLOGY 2011;54:38-49)

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The persistent infection with hepatitis C virus is a major cause of chronic liver disease worldwide. However, the morbidity associated with hepatitis C virus widely varies and depends on several host-related cofactors, such as age, gender, alcohol consumption, body weight, and co-infections. The objective of this review is to discuss three of these cofactors: steatosis, insulin resistance and oxidative stress. Although all may occur independently of HCV, a direct role of HCV infection in their pathogenesis has been reported. This review summarizes the current understanding and potential molecular pathways by which HCV contributes to their development.

Background: While PD-1/L1 blockade is an effective therapeutic approach for many patients with solid and hematologic malignancies, it is not sufficient to induce tumor regressions in the majority of patients. Optimal T cell responses require T cell receptor activation and co-stimulation, which can be provided via ligation of tumor necrosis factor receptor family members, such as OX40. Binding of OX40 by OX40L in the presence of a recognized antigen promotes CD4+ and CD8+ T cell expansion, enhances memory responses and inhibits regulatory T cell function. mRNA-2416 is a novel mRNA-based lipid nanoparticle therapeutic agent that expresses the wild type human OX40L. Preclinical in vivo anti-tumor activity of a murine mRNA-2416 surrogate and synergy with anti-PD-L1 antibodies in syngeneic cancer models are observed (unpublished). Here we present the findings of a first-in-human study of mRNA-2416 monotherapy delivered intratumorally in solid tumor patients with accessible lesions. Methods: This study tested the safety and efficacy of mRNA-2416 administered every 2 weeks for up to 12 doses in a standard 3+3 phase 1 dose escalation in patients with locally advanced, recurrent or metastatic solid malignancy or lymphoma. Tumor biopsies were collected pre- and post-treatment and evaluated by quantitative immunofluorescence (QIF) and RNA sequencing to characterize OX40L expression and immune response following treatment. Results: As of November 13, 2019, 39 patients have been treated at 4 dose levels from 1-8 mg. mRNA-2416 was generally well-tolerated with no DLTs. 6 out of 39 patients experienced grade 3 treatment related AEs. Out of 14 patients with best overall response of stable disease by RECIST, 6 had stable disease for ≥ 14 weeks, and 4 had tumor shrinkage in the injected lesions. Analyses of paired biopsies from injected lesions by QIF showed increased OX40L protein expression as well as elevated T cell scores post-treatment. Activation of a pro-inflammatory gene expression response post-treatment was observed in many cases, including increased cytolytic activity scores, elevated PD-L1 expression, and stimulation of a T cell-inflamed gene expression profile predictive of anti-PD-1/L1 response. These findings were observed in patients with long duration on study or tumor shrinkage. Conclusion: Intratumoral mRNA-2416 is tolerable at all dose levels studied when given as monotherapy and analyses of tumor post-treatment demonstrate increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity. Taken together with the observation of preclinical in vivo synergy with PD-L1 blockade, these data support the evaluation of a combination of intratumoral mRNA-2416 with the anti-PD-L1 inhibitor durvalumab in solid tumors, which is ongoing in part B of this study. Citation Format: Antonio Jimeno, Shilpa Gupta, Ryan Sullivan, Khanh T. Do, Wallace L. Akerley, Ding Wang, Deanna Teoh, Kurt Schalper, Sima J. Zacharek, Jing Sun, Andressa S. Laino, Joshua Frederick, Honghong Zhou, William Randolph, Stephanie Pascarella, Lisa Johansen, Pamela S. Cohen, ROBERT S. MEEHAN, Todd M. Bauer. A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT032.