Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies

Abstract

H epatitis C virus (HCV) has emerged as the major etiological agent of liver disease. Approximately 170 million individuals are infected worldwide, and the majority are at risk for developing serious progressive liver disease, with HCV being the leading indication for liver transplantation. The HCV single-stranded RNA genome encodes a single polyprotein, which is cleaved by viral and cellular proteases to produce the structural proteins; core E1 and E2 and nonstructural proteins; p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. The only approved treatment for HCV infection is interferon-␣ in combination with ribavirin, which is toxic and only effective in 50% of individuals with genotype I infections. Clearly, there is a need for more effective therapies and for the development of prophylactic and/or therapeutic vaccines.Cellular and humoral responses are generated during acute infection, but they are insufficient to achieve viral clearance in the majority of individuals, with approximately 60%-80% of new infections becoming persistent. 1,2 Neutralizing antibody (nAb) responses often provide the first-line adaptive defense against infection by limiting virus spread. However, little is known about the impact of the humoral immune response on HCV pathobiology. Serum antibodies (Abs) from chronically HCVinfected individuals demonstrate broadly reactive neutralizing properties in vitro and yet fail to control viral infection in vivo. [3][4][5] The reasons for their lack of effect are poorly understood. HCV may escape neutralization by

Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles

“…Whether the mechanisms of cell entry during cell-to-cell spread are distinct from those during cell entry by an extracellular virion is unclear. Most notably, there is conflicting data on whether cell-to-cell spread is CD81 independent (22,38,41) or not (7). OCLN knockdown has been reported to reduce cell-to-cell transmission by 2-to 3-fold in an assay in which spread, despite the presence of neutralizing antibodies in the supernatant, was defined as occurring cell to cell (7).…”

Entry and replication of recombinant hepatitis C viruses in cell culture

“…Although the quantified contribution of this cell-to-cell transmission and its modalities are still disputed, it can be evidenced in several systems. Usually, cell-to-cell transmission is evaluated between two co-cultured cell populations, one population of producer cells infected beforehand and one population of target cells that can be easily tracked due to a chemical [186], or geneticallyencoded fluorescent marker [101,102]. Infected events in the second populations are considered as indicator of cell-to-cell transmission if the cell-free infectivity is blocked.…”

“…Infected events in the second populations are considered as indicator of cell-to-cell transmission if the cell-free infectivity is blocked. This last condition can be 13 achieved by using saturating concentrations of neutralizing antibodies [171,186,187], particular virus mutants or target cells [101], or by culturing the cells under an agarose overlay that prevents Brownian motion of cell-free viruses [102,171]. The dual cell-based reporter system developed by Jones et al…”

Hepatitis C virus infection in children and adolescents

“…Major obstacles to HCV vaccine development are the diversity of the virus, the ability of the virus to evade the immune response in infected individuals with high rates of mutation, and development of “quasispecies,” which are distinct but closely related HCV variants that can be present in a single individual 5, 137, 142. Additional immune‐evading strategies that have been identified include antibody avoidance, cytotoxic T lymphocyte escape, and a failure to initiate an appropriate T cell response during the beginning of infection, among others 143, 144, 145, 146, 147, 148. Despite these challenges, several investigations have demonstrated success in preclinical animal studies showing induction of both humoral and cellular immunity against HCV 149, 150.…”