Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo

Abstract

Previous work on hepatitis C virus (HCV) led to the discovery of a new form of virus particle associating virus and lipoprotein elements. These hybrid particles (LVP for lipo-viro-particles) are enriched in triglycerides and contain at least apolipoprotein B (apoB), HCV RNA and core protein. These findings suggest that LVP synthesis could occur in liver and intestine, the two main organs specialized in the production of apoB-containing lipoprotein. To identify the site of LVP production, the genetic diversity and phylogenetic relationship of HCV quasispecies from purified LVP, whole serum and liver biopsies from chronically infected patients were studied. HCV quasispecies from LVP and liver differed significantly, suggesting that LVP were not predominantly synthesized in the liver but might also originate in the intestine. The authors therefore searched for the presence of HCV in the small intestine. Paraffin-embedded intestinal biopsies from 10 chronically HCV-infected patients and from 12 HCV RNA-negative controls (10 anti-HCV antibody-negative and two anti-HCV antibody-positive patients) were tested for HCV protein expression. HCV NS3 and NS5A proteins were stained in small intestine epithelial cells in four of the 10 chronically infected patients, and not in controls. Cells expressing HCV proteins were apoB-producing enterocytes but not mucus-secreting cells. These data indicate that the small intestine can be infected by HCV, and identify this organ as a potential reservoir and replication site. This further emphasizes the interaction between lipoprotein metabolism and HCV, and offers new insights into hepatitis C infection and pathophysiology. INTRODUCTIONHepatitis C virus (HCV) infects over 170 million people worldwide and is a major cause of chronic liver infection, often leading to chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV possesses a single-stranded, positivesense RNA genome encoding a single polyprotein, and the virus has been classified in the family Flaviviridae with the flaviviruses and pestiviruses (Pringle, 1999). Although the flaviviruses infect many tissues in a large number of hosts from insects to primates, and replicate in numerous cell lines in vitro, HCV replication is extremely limited and occurs mainly in the human liver (Hoofnagle, 2002;Rice, 1996). Studies on the virus replication and biology have been hampered by the lack of an efficient and reliable cell culture system, and because chimpanzee is the only animal model. HCV may be envisioned as a flavivirus whose replication relies on specific cellular functions present in specific organs such as the liver. A recent report on replication of HCV subgenomic replicons, without production of virus particles, in non-hepatic epithelial human and mouse hepatoma cells indicates that the specific cellular factors required for translation and replication of HCV RNA are not restricted to hepatocytes or cells of human origin (Zhu et al., 2003). Therefore, the apparent tropism of HCV for hepatocytes is probably also determi...

Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo

“…However, attempts to infect human peripheral blood mononuclear cells (PBMCs) largely with cell culture-derived HCV failed (46), suggesting that HCV particles and/or RNA may adhere to these cells but not efficiently enter them. HCV proteins have also been detected in epithelial cells from intestinal tissue specimens collected from HCV-infected patients (47), and in vitro experiments provided evidence that they can enter cells of the Caco-2 epithelium-derived colorectal adenocarcinoma cell line (48).…”

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

“…Previous studies have shown tissue-specific variations in different viral models, including arenavirus sequences isolated from the same animal (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). To avoid this bias, ML29 was isolated only from sera of vaccinated animals.…”

Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis

“…The IHC studies were used successfully to identify the extra-hepatic sites for HCV infection in many tissues such as intestinal tissues (Deforges et al, 2004), pancreas (Yan et al, 2000b), kidney (Sansonno et al, 1997), adrenal glands (Yan et al, 2000b), spleen (Yan et al, 2000b), gall bladder (Yan et al, 2000b), heart (Yan et al, 2000a) and lymph nodes (Pal et al, 2006). Gut immune cells are intrinsically linked to the liver responses because there is a shared lymphocyte recirculation between the gut and liver through the portal circulation (Adams et al, 2008;Gualdi et al, 1996).…”