PLoS One. 2014 Apr 16;9(4):e95103.

Strong vaccine-induced CD8 T-cell responses have cytolytic function in a chimpanzee clearing HCV infection.

Verstrepen BE1, Verschoor EJ1, Fagrouch ZC1, Mooij P1, de Groot NG2, Bontrop RE2, Bogers WM1, Heeney JL3, Koopman G1.
  • 1Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
  • 2Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
  • 3Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

 

ABSTRACT:

A single correlate of effective vaccine protection against chronic HCV infection has yet to be defined. In this study, we analyzed T-cell responses in four chimpanzees, immunized with core-E1-E2-NS3 and subsequently infected with HCV1b. Viral clearance was observed in one animal, while the other three became chronically infected. In the animal that cleared infection, NS3-specific CD8 T-cell responses were observed to be more potent in terms of frequency and polyfunctionality of cytokine producing cells. Unique to this animal was the presence of killing-competent CD8 T-cells, specific for NS31258–1272, being presented by the chimpanzee MHC class I molecule Patr-A*03 01, and a high affinity recognition of this epitope. In the animals that became chronically infected, T-cells were able to produce cytokines against the same peptide but no cytolysis could be detected. In conclusion, in the animal that was able to clear HCV infection not only cytokine production was observed but also cytolytic potential against specific MHC class I/peptide-combinations.

PMID: 24740375

 

SUPPLEMENT:

Hepatitis C virus (HCV) infection forms a major global health problem. It is estimated that worldwide approximately 170 million people are chronically infected and that HCV causes chronic liver inflammation in 20% of the infected individuals. Chimpanzees are the only validated animal model to study HCV. Infection studies in these animals indicate that spontaneous clearance is associated with HCV specific T-cell responses and the formation of specific antibodies. For this reason prophylactic vaccine strategies have been focusing on the induction of these HCV specific responses. Vaccine induced antibodies can neutralize the virus and thereby prevent further spreading of the virus. Alternatively, cytotoxic T-lymphocytes (CTL) can kill cells that are already infected. It is currently believed that combining these two types of immune responses into a vaccine strategy is the best way to prevent infection.

So called DNA prime -MVA boost strategies have been successfully applied in HIV vaccine research to induce HIV neutralizing antibodies and CTL. Therefore, this strategy was adapted to HCV and evaluated in chimpanzees (Rollier, Hepatology, 2007). The vaccine induced strong HCV specific immune responses in the four immunized chimpanzees and, as shown by a delayed and decreased peak viremia, the vaccine modified the course of infection in all four animals. Despite these responses, only one animal cleared the infection shortly after exposure, while the other three animals became persistently infected (Rollier, Hepatology, 2007).

To investigate if the quality of the vaccine induced T-cells could explain the differential outcome between the animals, in depth analysis of specificity and functionality was performed. FACS based techniques were used to map specificity of the CD4 and CD8 T-cell responses. We did not find a unique peptide recognition pattern that could explain the differences in outcome of the course of the infection between the animals. When we analyzed functional properties of these T-cells, especially CD8 T-cells displayed functional disparities. Although HCV peptide specific cytokine responses were observed in all four animals, CTL function was only detected in the animal that had been able to clear its infection. The cytolytic response was directed against one peptide only (LGFGAYMSK) and this peptide was only bound efficiently by MHC class I molecule Patr-A*03:01 which was uniquely present in the animal that cleared the infection. And even though the same peptide was recognized in some of the other animals, they were only able to generate a cytokine response against the peptide, but no CTL response.

In conclusion, we observed that the induction of an effective CD8 cytotoxic T-cell response was associated with HCV clearance and that this response was only elicited in the context of peptide presentation by appropriate class-I molecules. Given the MHC class I variation in the target population, the observation described here should be considered in future vaccine design and ultimately personalized vaccines may be required for optimal protection.

Reference: Rollier et. al., Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity. Hepatology. 2007 Jun;45(6):1590
viral scheme
Figure 1

A. Induction of an effective T-cell response, characterized by cytotoxic capacity (red T-cell), is dependent on peptide presentation by the appropriate MHC class I molecule (A3). Presentation by other MHC class I molecules was observed to induce T-cells that were able to produce cytokines but had no cytotoxic capacity (yellow T-cells).
B. HCV clearance is associated with the presence of cytotoxic T-cells generated in the context of MHC class I molecule A3 (red-red), while viral persistence is observed when only cytokine producing T-cells (blue-yellow and green yellow) are induced.

 

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