Conceptualizing an HCV vaccine: the importance of T cell immunity.

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Mar 07, 2019
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An estimated 71 million people are chronically infected with HCV worldwide. Despite the availability of curative antivirals, a vaccine is necessary to prevent new HCV infections and re-infections in cured individuals. The limited host range of HCV, which infects only humans and chimpanzees, has made studying this virus in vivo challenging and hampered the development of a vaccine. Animal homologs of human viruses have been widely recognized as important and often the only alternative to study immunity and pathogenesis of human viruses that are strictly species-specific. Studies of Murine norovirus, Simian immunodeficiency viruses, and animal herpesviruses were immensely helpful in delineating the mechanisms their human homologs use to subvert host immunity and establish life-long persistence.

Since the last few years, the main focus of my lab has been to develop a meaningful surrogate model for HCV. Towards this, we isolated a rodent hepacivirus (RHV) strain from a feral rat trapped in New York City. It was critical to have a well characterized virus stock and therefore, we first developed a reverse genetic system for RHV to generate a homogenous inoculum for subsequent studies of infection and immunity. We then determined that RHV infection in a majority of laboratory rats, also the natural host of this virus, becomes chronic like HCV infection in humans. This was a remarkable finding since the testing of HCV vaccination concepts warrants a model that is fully susceptible to HCV-like viral persistence.

Although the immune correlates of HCV infection outcomes are poorly defined, subversion of T cell immunity is a hallmark of persistent HCV infection in humans. The first step for us, therefore, was to characterize the nature of T cell immunity associated with persistent RHV infection in rats. Our data shows that RHV infection induces expansion of virus-specific CD8+ T cells but these cells then rapidly contract in absence of strong CD4+ T cell help. We then hypothesized that the pre-infection priming of T cells should be able to prevent T cell subversion and protect against RHV persistence. Towards this, we vaccinated rats using a recombinant Adenovirus expressing RHV non-structural proteins. Interestingly, a single dose of T cell vaccine protected a majority of rats (>60%) against RHV persistence. We then used in vivo cell depletion experiments to confirm that the clearance of challenge virus requires recall responses of both vaccine-primed CD4+ and CD8+ T cells. In summary, we showed that T cell vaccination can protect against HCV-like virus persistence. However, several important questions remain unanswered: Why do some vaccinated rats failed to clear the virus? What factors facilitate virus escape from CD8+ T cells? How broad is the T cell vaccine induced immunity (HCV genotypes are genetically diverse) and, can we enhance the T cell vaccine efficacy by complementary B cell immunization?

I believe that further dissection of vaccine and RHV infection conferred immunity is necessary for the identification of immune-correlates of protection against hepacivirus persistence, and this knowledge is crucial for conceptualizing an effective HCV vaccine. Additionally, the nature of RHV persistence in rats is unique compared to other murine models of RNA virus persistence (like LCMV or norovirus), and therefore studies of RHV infection in rats may reveal unique mechanisms of immune failure associated with persistence of hepatotropic viruses.  

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Amit Kapoor

Associate Professor , The Research Institute at Nationwide Children's Hospital/The Ohio State University

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Amit Kapoor 2 months ago