Journal
JOURNAL OF VIROLOGY
Volume 92, Issue 23, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01219-18
Keywords
HCV; innate immunity; pDCs
Categories
Funding
- Instituto de Salud Carlos III [PI12/02283, PI16/00684, CPII014/00025, FI14/00431]
- Consejeria de Salud y Bienestar Social of Junta de Andalucia through the Nicolas Monardes program [C-0032/17]
- Red Tematica de Investigacion Cooperativa en SIDA [RD12/0017/0029, RD16/0025/0020]
- Spanish Ministry of Education [FPU13/02451]
- Miguel Servet program of the Instituto de Salud Carlos III [CP14/00121]
- European Regional Development Fund (ERDF)
- Instituto de Salud Carlos III
- PLATESA from Comunidad de Madrid/FEDER [SAF2014-52400-R, SAF2017-87846-R, S2013/ABI-2906]
- Fundacion Ramon Areces
- Banco Santander
- Accion Estrategica en Salud, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica 2008-2011, Instituto de Salud Carlos III, Fondos FEDER
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Plasmacytoid dendritic cells (pDCs) are innate immune cells with high antiviral activity triggered by Toll-like receptor 7 (TLR-7) and TLR-9 stimulation. Moreover, they are important mediators between innate and adaptive immunity. Although nowadays there is available an effective therapeutic arsenal against hepatitis C virus (HCV), a protective vaccine is not available. We have analyzed the pDCs' response to HCV infection in a hepatitis C virus (HCV)-Huh7.5 virus-cell system, which allows completion of the virus infectious cycle. pDCs were cocultured following human immunodeficiency virus (HIV) aldrithiol-2 (AT-2 [TLR-7 agonist]) inactivation and CpG (TLR-9 agonist) stimulation. We employed three virus derivatives-wild-type Jc1, interferon (IFN)-resistant virus IR, and high-replicative-fitness virus P100-in order to explore additional IFN-alpha-related virus inhibition mechanisms. pDCs inhibited HCV infectivity and replication and produced IFN-alpha. After TLR-7 and TLR-9 stimulation, inhibition of infectivity and IFN-alpha production by pDCs were enhanced. TLR-7 stimulation drove higher TNF-related apoptosis-inducing ligand (TRAIL) expression in pDCs. Additionally, TLR-7- and TLR-9-stimulated pDCs exhibited a mature phenotype, improving the antigen presentation and lymph node homing-related markers. In conclusion, pDCs could serve as a drug target against HCV in order to improve antiviral activity and as an enhancer of viral immunization. IMPORTANCE We implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs' behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-alpha, but also through additional mechanisms associated with pDC maturation. We provided evidence that TLR agonists can enhance antiviral pDCs' function and can induce phenotypic changes that may facilitate the interplay with other immune cells. These findings suggest the possibility of including TLR agonists in the strategies of HCV vaccine development.
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