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Chapter 20 : Immune Responses to Persistent Viruses
Category: Immunology; Clinical Microbiology
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This chapter discusses some general principles regarding immune responses during chronic viral infections. A broad consideration of viral pathogenesis and antiviral immune responses is crucial to bear in mind when examining these persisting viral infections. In discussing immune responses to persisting viruses, it is important to keep in mind the strategies exploited by different viruses to facilitate persistence. The immune response is capable of effectively controlling or eradicating a large number of viral infections and it does so by using a variety of effector mechanisms including cytotoxic T cells, antibodies, cytokines (from the innate and adaptive immune responses), among others. The pathology upon infection with viruses like chronic lymphocytic choriomeningitis virus (LCMV) or hepatitis C virus (HCV) is therefore largely immune-mediated, rather than virus-mediated. While the focus of this chapter is on chronic viral infections that cause disease, it may be that the majority of persisting viruses coexist effectively with the immune system and cause little or no disease in healthy people. Persistent virus infections represent a major challenge for the future, both in terms of designing vaccines and therapies and in terms of defining the fundamental immunology. The key features outlined here provide a reasonable basis for exploring the responses to new viruses as they emerge, and for the design of new therapies for prevention and treatment of existing viruses.
Host virus dynamics in acute resolving and persistent infection. The upper panel shows a setting where LCMV or HCV sets up acute infection that is then rapidly contained. In this case, robust and functional T-cell responses are induced and sustained over time. The lower panel shows a dynamic with long-term persistence of virus. In this case, T-cell responses are also induced but are not effectively sustained either physically or functionally. The immunologic correlates are shown on the right-hand side. These vary slightly between HCV and LCMV as indicated. The timescales are also different between the two viruses due to the very long period (weeks) after HCV infection prior to the initiation of the immune response.
Distinct T-cell differentiation pathways associated with different virologic outcomes. After acute infection, if the virus is cleared effector T cells will eventually revert to a central memory phenotype (Top). If the virus is not cleared, two possible outcomes exist: either expansion of the effector memory pool, typically associated with subclinical virus persistence (Middle), or a program of T-cell exhaustion, typically associated with high level virus carriage (Bottom). The relationships between the phenotypes are not fully defined and the surface markers shown vary between infections and between mice and humans to some extent.
Stages of T-cell exhaustion. CD8 T-cell exhaustion is characterized by hierarchical stages of T-cell dysfunction in comparison with a resting memory cell. The top depicts the properties of a functional memory CD8 T cell generated following an acute/cleared infection or vaccination. The bottom depicts the stages or degrees of exhaustion that can occur when a virus persists. Decreased function and increased apoptosis are associated with higher viral load, lower CD4 T-cell help, and increased expression of inhibitory receptors such as PD-1.
T-cell escape observed through an HLA “footprint.” Sequencing of dominant viral sequences in a cross-sectional manner can reveal prototypical escape mutations. Sequences are indicated according to a specific HLA (X in the diagram; e.g., B27). If an excess of mutations is seen at a specific site in the HLA-X group there is statistical evidence for T-cell-mediated immune pressure.
HLA footprinting is limited by many variables. Although T-cell mediated selection may occur, the footprinting approach relies on the sequence of events indicated in the black diagrams. If a viral region is highly conserved, highly targeted by a single response, mutates under selection pressure and reverts upon transmission then a footprint is typically visible. However, intrinsic variation, geographical linkage of HLA and variant, failure of reversion, multiple selection events, or failure of selection can all lead to loss of power of the approach.
Dynamics of T-cell responses during diverse types of persisting viral infections. T-cell frequencies and the dynamics of maintenance differ widely during chronic infections. Viruses that persist at a low level may be associated with T-cell memory inflation. This group includes viruses such as CMV and many others shown. Viruses where exhaustion may dominate include LCMV, HBV, and HCV, but this may also be true in many other settings and even for the same infection differing between specific epitopes.
Strategies to facilitate persisting viral infection
Properties of functional memory T cells generated following acute infection or vaccination
Molecular pathways associated with T cell exhaustion during chronic viral infection