Immune protection against reinfection with nonprimate hepacivirus

Abstract

Hepatitis C virus (HCV) displays a restricted host species tropism and only humans and chimpanzees are susceptible to infection. A robust immunocompetent animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control, and prophylactic vaccine development. The closest homolog of HCV is the equine nonprimate hepacivirus (NPHV), which shares similar features with HCV and thus represents an animal model to study hepacivirus infections in their natural hosts. We aimed to dissect equine immune responses after experimental NPHV infection and conducted challenge experiments to investigate immune protection against secondary NPHV infections. Horses were i.v. injected with NPHV containing plasma. Flow cytometric analysis was used to monitor immune cell frequencies and activation status. All infected horses became viremic after 1 or 2 wk and viremia could be detected in two horses for several weeks followed by a delayed seroconversion and viral clearance. Histopathological examinations of liver biopsies revealed mild, periportally accentuated infiltrations of lymphocytes, macrophages, and plasma cells with some horses displaying subclinical signs of hepatitis. Following viral challenge, an activation of equine immune responses was observed. Importantly, after a primary NPHV infection, horses were protected against rechallenge with the homologous as well as a distinct isolate with only minute amounts of circulating virus being detectable.hepatitis C virus | nonprimate hepacivirus | infection | immune protection | rechallenge H epatitis C virus (HCV) infections constitute a major global health problem with ∼130 million people being chronically infected (1). Once infected, 70-90% of individuals progress to chronicity, rendering HCV the leading cause of liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (2). HCV is a blood-borne, positive-stranded RNA virus classified to the family of Flaviviridae within the genus Hepacivirus. Seven different HCV genotypes and numerous subtypes have been described, which differ on the nucleotide level by ∼30-35% between different genotypes and maximally 30% between subtypes (3). Furthermore, within infected individuals the virus circulates as a population of closely related but distinct genomes (4). Recently, significant progress has been made regarding the treatment of HCV with the implementation of direct-acting antiviral (DAA) drugs, which can be administered as all-oral IFN-free therapeutics and should help to reduce the global burden of HCV infections (5). However, there are still many caveats, including high treatment costs and the risk of reinfection after successful therapy, which is a problem especially in patient populations with frequent exposure to HCV. Furthermore, the inadequacy of current HCV screening programs often results in late diagnosis of chronic HCV infection and subsequent proceeding to end-stage liver diseases (6). All of these challenges highlight the necessity for a prophylactic vaccine against HCV, ...

Chronic equine hepacivirus infection in an adult gelding with severe hepatopathy

“…Additionally, it has been reported that experimental infections have a mild effect on the liver (Pfaender et al . ). Although NGS revealed presence of other infectious agents like Actinomyces ruminicola , these are not known to cause any disease in equids.…”

First detection and frequent occurrence of Equine Hepacivirus in horses on the African continent

“…In contrast to HCV, circulating EqHV strains have been described as closely related (Pronost et al, 2017) and an established immune response against primary viral challenge protects the host against reinfection (Pfaender et al, 2017).…”

Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model

“…The nonprimate hepaciviruses or equine hepaciviruses are interesting given that they remain the closest genetic relatives of HCV, and share many features of its natural history . However, they mostly cause acute resolving infection with no clinical disease in horses, and studies are limited by the number of animals, expenses, and lack of species‐specific research reagents. We therefore focused our efforts on developing a tractable lab rodent surrogate model for HCV and selected the rat hepacivirus RHV‐rn1.…”