Abstract
Hepatitis C virus (HCV) is the etiologic agent of chronic liver disease, hepatitis C. Spontaneous resolution of viral infection is associated with vigorous HLA class I- and class II-restricted T cell responses to multiple viral epitopes. Unfortunately, only 20% of patients clear infection spontaneously, most develop chronic disease and require therapy. The response to chemotherapy varies, however; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success. Vector-mediated vaccination with multi-epitope-expressing DNA constructs alone or in combination with chemotherapy offers an additional treatment approach. Gene sequences encoding validated HLA-A2- and HLA-DRB1-restricted epitopes were synthesized and cloned into an expression vector. Dendritic cells (DCs) derived from humanized, HLA-A2/DRB1 transgenic (donor) mice were transfected with these multi-epitope-expressing DNA constructs. Recipient HLA-A2/DRB1 mice were vaccinated s.c. with transfected DCs; control mice received non-transfected DCs. Peptide-specific IFN-γ production by splenic T cells obtained at 5 weeks post-immunization was quantified by ELISpot assay; additionally, the production of IL-4, IL-10 and TNF-α were quantified by cytokine bead array. Splenocytes derived from vaccinated HLA-A2/DRB1 transgenic mice exhibited peptide-specific cytokine production to the vast majority of the vaccine-encoded HLA class I- and class II-restricted T cell epitopes. A multi-epitope-based HCV vaccine that targets DCs offers an effective approach to inducing a broad immune response and viral clearance in chronic, HCV-infected patients.
Highlights
Hepatitis C virus (HCV), a small single-stranded RNA virus, is a major cause of chronic liver disease
The standard of care for patients consisted of pegylated-interferon and ribavirin administered over a 48-week period, which results in a sustained virologic response (SVR) in 45–50% of those infected with HCV genotype 1 [6]
The Dendritic cells (DCs) population, enriched to
Summary
Hepatitis C virus (HCV), a small single-stranded RNA virus, is a major cause of chronic liver disease. Cirrhosis due to chronic HCV is the leading indicator for liver transplantation in the U.S The socioeconomic burden of hepatitis C-associated diseases in the U.S is estimated at a staggering $7 billion/year [5]. The standard of care for patients consisted of pegylated-interferon and ribavirin administered over a 48-week period, which results in a sustained virologic response (SVR) in 45–50% of those infected with HCV genotype 1 (the principal causative agent in the US) [6]. New therapeutic approaches that include direct-acting anti-viral agents, for example, NS3-4A protease inhibitors (i.e., boceprevir or telaprevir) and NS5B polymerase inhibitors (e.g., sofosbuvir), administered in various combinations with or without pegylated-interferon or ribavirin, increase the SVR significantly [7].
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