Vaccination to prevent T cell subversion can protect against persistent hepacivirus infection

Alex S Hartlage,Sheetal Trivedi,Piyush Dravid,Christopher M Walker,Himanshu Sharma,Satyapramod Murthy,Amit Kapoor,Arvind Kumar

doi:10.1038/s41467-019-09105-0

Alex S Hartlage, Sheetal Trivedi + Show 6 more

Open Access

https://doi.org/10.1038/s41467-019-09105-0

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Abstract

Efforts to develop an effective vaccine against the hepatitis C virus (HCV; human hepacivirus) have been stymied by a lack of small animal models. Here, we describe an experimental rat model of chronic HCV-related hepacivirus infection and its response to T cell immunization. Immune-competent rats challenged with a rodent hepacivirus (RHV) develop chronic viremia characterized by expansion of non-functional CD8+ T cells. Single-dose vaccination with a recombinant adenovirus vector expressing hepacivirus non-structural proteins induces effective immunity in majority of rats. Resolution of infection coincides with a vigorous recall of intrahepatic cellular responses. Host selection of viral CD8 escape variants can subvert vaccine-conferred immunity. Transient depletion of CD8+ cells from vaccinated rats prolongs infection, while CD4+ cell depletion results in chronic viremia. These results provide direct evidence that co-operation between CD4+ and CD8+ T cells is important for hepacivirus immunity, and that subversion of responses can be prevented by prophylactic vaccination.

Highlights

Efforts to develop an effective vaccine against the hepatitis C virus (HCV; human hepacivirus) have been stymied by a lack of small animal models
Using rats infected with rodent hepacivirus (RHV) as a surrogate model of chronic HCV infection in humans, we demonstrate that (a) spontaneous hepacivirus persistence is associated with a transient virus-specific CD8+ T cell response that develops in the absence of strong CD4+ T cell help, (b) pre-exposure priming of virus-specific T cells by an adenovirus vector expressing non-structural viral proteins prevents virus persistence in majority of animals, and (c) antibody-mediated depletion of vaccine-primed T cells abrogates protective immunity after challenge
Viremia and serum ALT levels, a marker of acute liver damage, were largely stable after infection, with only a small drop in serum viral titers (~1–2 log) occurring 6–10 weeks after challenge. This partial suppression of viremia was temporally associated with the onset of IFNγ enzyme linked immunospot (ELISpot) responses targeting the RHV core protein in both liver and spleen (Fig. 1b)

Summary

Introduction

Efforts to develop an effective vaccine against the hepatitis C virus (HCV; human hepacivirus) have been stymied by a lack of small animal models. We describe an experimental rat model of chronic HCV-related hepacivirus infection and its response to T cell immunization. Immune-competent rats challenged with a rodent hepacivirus (RHV) develop chronic viremia characterized by expansion of non-functional CD8+ T cells. A T cell vaccine that primed HCVspecific CD4+ and CD8+ T cell responses in chimpanzees led to suppressed viremia and accelerated virus control after experimental challenge[25] Despite these circumstantial lines of evidence, a direct causal relationship between a host T cell response and primary HCV infection outcome has yet to be established. RHV spontaneously persists at high frequency in rats, the natural host of the virus This occurs despite the activation of hepatic innate and adaptive immune processes to chronic HCV in humans[28,30]. Protective mechanisms that fail to control RHV in rats and whether they can be successfully elicited via immunization has yet to be investigated

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