Both innate and adaptive immunity mediate protective immunity against hepatitis C virus infection in chimpanzees

Abstract

Understanding the immunological correlates associated with protective immunity following HCV re-exposure is a prerequisite for the design of effective HCV vaccines and immunotherapeutics. In this study we performed a comprehensive analysis of the innate and adaptive immunity following HCV re-exposure of two chimpanzees that had previously recovered from HCV-JFH1 infection. One of the chimpanzees, CH10274, became protected from active viremia by repeatedly challenges with homologous JFH1cc and developed neutralizing antibodies, but was later infected with high-level viremia by a heterologous challenge with H77 virus that persisted for more than one year. The other chimpanzee, CH10273 was protected from a similar, heterologous H77 challenge without any evidence of neutralizing antibodies. Peripheral HCV-specific T cell responses were present in both chimpanzees after challenges and interestingly the overall magnitude of response was lower in uninfected CH10273, which, however, exhibited a more robust CD8+ T cell response. CH10273 showed higher hepatic expression of CD8 and CD56 (natural killer) markers than CH10274 did shortly after inoculation with H77. The heightened T cell response was associated with an enhanced hepatic production of interferons (both type I and II) and interferon-stimulated genes (ISGs) in CH10273. Therefore protection or clearance of HCV reinfection upon heterologous re-challenge depends on the activation of both intrahepatic innate and cellular immune responses. Furthermore, our results suggest that serum neutralizing antibodies may contribute to early control of viral replication and spread after homologous HCV re-challenges but may not be sufficient for long-term protective immunity. Conclusion Our study shows that protective immunity against HCV re-infection is orchestrated by a complex network of innate and adaptive immune responses.

Hepatic immunopathology during occult hepacivirus re-infection

“…Innate immune cells can also play major roles in modulating Hepacivirus infections (Barth et al, 2011; Gonzalez et al, 2010; Kanto and Hayashi, 2007; Manickam et al, 2016; Werner et al, 2013), and innate activation is a hallmark of disease. In order to understand the role of innate immunity in hepacivirus re-infection, we phenotyped NK cells and DCs in the blood of re-challenged animals.…”

“…In addition to T cell responses, innate immune cells such as NK cells contribute significantly to anti-hepacivirus immunity; however, they are also associated with increased pathology (Barth et al, 2011; Kanto, 2008; Manickam et al, 2016; Yamanaka et al, 2002; Zhou et al, 2014). In animal 01–10, more than 2-fold increases in levels of activated NK cells (Ki-67 + NK cells) were observed at day 7.…”

Current progress in development of hepatitis C virus vaccines

“…Although B cell immunity, as represented by neutralizing antibodies, may contribute to host defense against HCV, its role in viral clearance is less clear 21,28–31 . In particular, the envelope proteins of HCV are not very immunogenic, as evidenced by a slow and weak antibody response during primary infection 32,33 .…”

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus

“…Currently, limitations of small-primate models hamper the development of HCV vaccines and affordable antiviral drugs. Chimpanzees have been used as a uniquely reliable animal for HCV infection in past decades (2), significantly contributing to defining the infection natural history, pathogenesis, immune response, and rechallenge of HCV (3)(4)(5)(6). However, the utility of chimpanzees has been more and more restricted by ethical concerns, and though rare, the use of this primate model in medical studies is extremely costly (2).…”

“…The negative and positive controls were 1640 medium and phytohemagglutinin (PHA), respectively. The number of spot-forming cells (SFC) was normalized to the number of SFC per 10 6 PBMCs. Statistical analysis.…”