Tree shrew bone marrow–derived mesenchymal stem cells express CD81, OCLN, and miR‐122, facilitating the entire hepatitis C virus life cycle

Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated cirrhosis, and hepatocellular carcinoma worldwide. At present, there is no prophylactic vaccine against HCV due to the lack of in vivo and in vitro model systems. Although most recombinants of all major HCV genotypes replicate in Huh‐7 cell line and derivatives, these cells are human hepatoma‐derived cell line. Therefore, the development of un‐tumor‐derived cell systems facilitating the entire HCV life cycle is urgently needed. In this study, we aimed to establish a novel tree shrew‐derived bone marrow–derived mesenchymal stem cell (BM‐MSC) system to reconstruct the HCV life cycle. We transduction cluster of differentiation 81 (CD81), occludin (OCLN), and microRNA‐122 (miR‐122) into BM‐MSCs, then used a well‐established HCV, produced from the J6/JFH1‐Huh7.5.1 culture system, to infect the cells. We observed that BM‐MSCs transduction with CD81/OCLN or CD81/OCLN/miR‐122 support HCV RNA replication and infectious virus production. We also found that the addition of exogenous vascular endothelial growth factor (VEGF) can enhance HCV infectivity in BM‐MSCs, with HCV virus load up to 105 copies/mL. In conclusion, we identified the minimum essential factors required for HCV replication in tree shrew‐derived nonhuman nonhepatic BM‐MSCs. Further, we identified that exogenous addition of VEGF, and exogenous expression of CD81, OCLN, and miR‐122, facilitates efficient viral replication and production of infectious particles. Our results describe a novel cell system capable of supporting the entire HCV life cycle, which may provide an essential tool for anti‐HCV drug discovery, vaccine development, and study of pathogenesis.

Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

“…They are considered as “molecular facilitators” connecting extracellular and cytoplasmic signaling elements [ 47 ]. In this context, CD81 is known to facilitate cells adhesion or fusion in the frame of viral infection [ 48 , 49 ]. The large extracellular loop EC2 (LEL) of CD81 can interact with a variety of proteins, so as to facilitate cellular interaction and capture.…”

The epidemiology and disease burden of children hospitalized for viral infections within the family Flaviviridae in China: A national cross-sectional study

“…We found that the reported hospitalized cases of HCV were also mainly distributed in northwest (47.37%) and central China (36.84%). Currently, there are no safe and effective vaccines or antiviral drugs against HCV available for children [53,54]. In particular, the most significant hurdle to develop an HCV vaccine is the high mutation rate of the virus, facilitating its ability to escape the host immune response [55].…”

Characteristics of Angiotensin I-converting enzyme 2, type II transmembrane serine protease 2 and 4 in tree shrew indicate it as a potential animal model for SARS-CoV-2 infection

“…It can be used for biomedical studies of various human diseases [5][6][7]. In recent years, several virus infection models, including influenza B [8], Zika virus [9], hepatitis C virus [10], and avian H5N1/ H9N2 influenza viruses [11,12], have been investigated by using tree shrews. Other human diseases, such as retinal vein pulsation and glaucoma of the visual system [13][14][15], myocardial ischemia and atherosclerosis of the cardiovascular system [16,17], nonalcoholic fatty liver [18], diabetic nephropathy [19] and obesity [20] of metabolism, cancers [21,22], Alzheimer's disease [23] and depression [24], all used tree shrews as disease models for their studies.…”