phaidra.vetmeduni.ac.at o:2072 DOI 10.1128/spectrum.01686-22 Dose-Dependent Hepacivirus Infection Reveals Linkage between Infectious Dose and Immune Response More than 70 million people worldwide are still infected with the hepatitis C virus 30 years after its discovery, underscoring the need for a vaccine. To develop an effective prophylactic vaccine, detailed knowledge of the correlates of protection and an immunocompetent surrogate model are needed. In this study, we describe the minimum dose required for robust equine hepacivirus (EqHV) infection in equids and examined how this relates to duration of infection, seroconversion, and transcriptomic responses. To investigate mechanisms of hepaciviral persistence, immune response, and immune-mediated pathology, we inoculated eight EqHV naive horses with doses ranging from 1-2 copies to 1.3 × 106 RNA copies per inoculation. We characterized infection kinetics, pathology, and transcriptomic responses via next generation sequencing. The minimal infectious dose of EqHV in horses was estimated at 13 RNA copies, whereas 6 to 7 copies were insufficient to cause infection. Peak viremia did not correlate with infectious dose, while seroconversion and duration of infection appeared to be affected. Notably, seroconversion was undetectable in the low-dose infections within the surveillance period (40 to 50 days). In addition, transcriptomic analysis revealed a nearly dose-dependent effect, with greater immune activation and inflammatory response observed in high-dose infections than in low-dose infections. Interestingly, inoculation with 6-7 copies of RNA that did not result in productive infection, but was associated with a strong immune response, similar to that observed in the high-dose infections. IMPORTANCE We demonstrate that the EqHV dose of infection plays an important role for inducing immune responses, possibly linked to early clearance in high-dose and prolonged viremia in low-dose infections. In particular, pathways associated with innate and adaptive immune responses, as well as inflammatory responses, were more strongly upregulated in high-dose infections than in lower doses. Hence, inoculation with low doses may enable EqHV to evade strong immune responses in the early phase and therefore promote robust, long-lasting infection. eng Hepatitis-C Virus; T-Cell Responses; Nonprimate Hepacivirus; Hcv; Chimpanzees; Clearance; Viremia; Seroconversion; Transmission; Prevalence 2023-09-05T13:50:15.961Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Gömer;André; FN:André Gömer X-ORCID:https://orcid.org/0000-0002-4567-0441 END:VCARD BEGIN:VCARD VERSION:3.0 N:Todt;Daniel; FN:Daniel Todt X-ORCID:https://orcid.org/0000-0002-3564-1014 END:VCARD BEGIN:VCARD VERSION:3.0 N:Steinmann;Eike; FN:Eike Steinmann X-ORCID:https://orcid.org/0000-0002-3654-9965 END:VCARD BEGIN:VCARD VERSION:3.0 N:Feige;Karsten; FN:Karsten Feige END:VCARD BEGIN:VCARD VERSION:3.0 N:Cavalleri;Jessika M. V.; FN:Jessika M. V. Cavalleri X-ORCID:https://orcid.org/0000-0002-8575-7402 END:VCARD BEGIN:VCARD VERSION:3.0 N:Baumgärtner;Wolfgang; FN:Wolfgang Baumgärtner END:VCARD BEGIN:VCARD VERSION:3.0 N:Reinecke;Birthe; FN:Birthe Reinecke END:VCARD BEGIN:VCARD VERSION:3.0 N:Nocke;Maximilian K.; FN:Maximilian K. Nocke X-ORCID:https://orcid.org/0000-0003-4632-525X END:VCARD BEGIN:VCARD VERSION:3.0 N:Puff;Christina; FN:Christina Puff END:VCARD BEGIN:VCARD VERSION:3.0 N:Delarocque;Julien; FN:Julien Delarocque X-ORCID:https://orcid.org/0000-0002-4598-3499 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 789213 https://phaidra.vetmeduni.ac.at/o:2072 https://phaidra.vetmeduni.ac.at/api/object/o:2072/thumbnail LOMv1.0 discipline