Cellular immune responses against hepatitis C virus: the evidence base 2002

Abstract

Hepatitis C virus (HCV) is an RNA virus which is estimated to persistently infect about 170 million people worldwide. After acute infection, there is an initial period during which long-term outcome is decided. There is strong evidence that the cellular immune responses, involving both CD4+ and CD8+ T lymphocytes, are involved at this stage and it is their effectiveness which determines outcome. What is not understood is what determines their effectiveness. The most important component of this is likely to be some aspect of epitope selection, itself dictated by host MHC. Thus, to understand host immunity to HCV, we need to have a detailed understanding of the peptides involved in T lymphocyte responses. In this review, we discuss the peptide epitopes that have been identified so far, and their potential significance. We relate this to a scheme of host defence which may be useful for understanding natural and vaccine-induced immunity.

Fig. 1

A simple model for the role of T cell epitope selection in HCV outcome. (a) T cell responses are induced optimally in lymphoid tissue and migrate to the liver to suppress viral replication (positive loop). The liver environment, acccompanied by a high viral load serves to attenuate T cell responses (negative loop). High viral loads will also tend to promote escape. (b) An optimal ‘efficient’ response rapidly reduces viral load and thus accentuates the positive over the negative loop. The mechanism behind ‘efficiency’ is not well defined, but includes breadth, vigour, avidity (i.e. the ability to recognize infected cells sensitively), good effector function and targeting of ‘constrained’ epitopes. (c) An inefficient response fails to lower viral load rapidly and enters the negative loop. In this example the responses lack vigour or avidity, and are then attenuated further in the face of maintained viral loads. (d) An inefficient response fails to lower viral load early and allows for the emergence of escape variants. This will be promoted if the response is targeted at epitopes which can escape rapidly, or if the response is very highly focused.

Fig. 1

A simple model for the role of T cell epitope selection in HCV outcome. (a) T cell responses are induced optimally in lymphoid tissue and migrate to the liver to suppress viral replication (positive loop). The liver environment, acccompanied by a high viral load serves to attenuate T cell responses (negative loop). High viral loads will also tend to promote escape. (b) An optimal ‘efficient’ response rapidly reduces viral load and thus accentuates the positive over the negative loop. The mechanism behind ‘efficiency’ is not well defined, but includes breadth, vigour, avidity (i.e. the ability to recognize infected cells sensitively), good effector function and targeting of ‘constrained’ epitopes. (c) An inefficient response fails to lower viral load rapidly and enters the negative loop. In this example the responses lack vigour or avidity, and are then attenuated further in the face of maintained viral loads. (d) An inefficient response fails to lower viral load early and allows for the emergence of escape variants. This will be promoted if the response is targeted at epitopes which can escape rapidly, or if the response is very highly focused.

Fig. 1

A simple model for the role of T cell epitope selection in HCV outcome. (a) T cell responses are induced optimally in lymphoid tissue and migrate to the liver to suppress viral replication (positive loop). The liver environment, acccompanied by a high viral load serves to attenuate T cell responses (negative loop). High viral loads will also tend to promote escape. (b) An optimal ‘efficient’ response rapidly reduces viral load and thus accentuates the positive over the negative loop. The mechanism behind ‘efficiency’ is not well defined, but includes breadth, vigour, avidity (i.e. the ability to recognize infected cells sensitively), good effector function and targeting of ‘constrained’ epitopes. (c) An inefficient response fails to lower viral load rapidly and enters the negative loop. In this example the responses lack vigour or avidity, and are then attenuated further in the face of maintained viral loads. (d) An inefficient response fails to lower viral load early and allows for the emergence of escape variants. This will be promoted if the response is targeted at epitopes which can escape rapidly, or if the response is very highly focused.

Fig. 1

A simple model for the role of T cell epitope selection in HCV outcome. (a) T cell responses are induced optimally in lymphoid tissue and migrate to the liver to suppress viral replication (positive loop). The liver environment, acccompanied by a high viral load serves to attenuate T cell responses (negative loop). High viral loads will also tend to promote escape. (b) An optimal ‘efficient’ response rapidly reduces viral load and thus accentuates the positive over the negative loop. The mechanism behind ‘efficiency’ is not well defined, but includes breadth, vigour, avidity (i.e. the ability to recognize infected cells sensitively), good effector function and targeting of ‘constrained’ epitopes. (c) An inefficient response fails to lower viral load rapidly and enters the negative loop. In this example the responses lack vigour or avidity, and are then attenuated further in the face of maintained viral loads. (d) An inefficient response fails to lower viral load early and allows for the emergence of escape variants. This will be promoted if the response is targeted at epitopes which can escape rapidly, or if the response is very highly focused.