Viral infection and immunity: balancing protection and pathology

Abstract

This series contains five reviews on aspects of host–virus interactions. We have selected four viruses that cause persistent infection—namely the hepatitis viruses B and C (HBV and HCV), human immunodeficiency virus (HIV) and cytomegalovirus (CMV). We also are discussing the flaviruses which cause encephalitis; the latter share common pathology—some of which is immune mediated—and although the infections are usually acute, the sequelae may be very long term. There are many other viruses with significant impacts on human health we could have also included—many of the herpes virus family have links with severe disease and cancer (e.g. Epstein Barr Virus and HHV-8), but it is hoped the reader through this small selection will get a flavour of the complex host–virus interactions which are being unpicked by researchers around the world, and some of the methods being used to develop new diagnostic and prognostic tools, treatments and vaccines. Although the viruses are very different genetically and indeed the diseases are clinically diverse, there are some shared elements of pathogenesis which link them together. Four are highlighted below: Much of the tissue damage in such infections may be host mediated: although viruses may cause direct cytopathic effects, it is also clear that in chronic hepatitis, immune-mediated damage to the liver is a major player. This is particularly obvious in hepatitis B infection. Even in HIV, where there is relative immunodeficiency, immune activation may contribute to the progression towards acquired immuno-deficiency syndrome (AIDS), and there is an important immunopathology associated with viral encephalitides. The focus of many researchers is subtly shifting from adaptive mechanisms towards innate immunity: it is clear that adaptive responses such as antibody and T cells play a huge role in containment of persistent infections. However, to understand the differential outcomes of infection, a better definition of the innate response is required. This is very obvious in the case of hepatitis C, where host genetics points the finger at the interferon lambda gene IL28B (see accompanying review). Overall, the view that robust protective immunity is a team game for the immune system is clearly emerging. Low levels of virus in tissues are very hard to eliminate and provide a complex target for therapy: Hepatitis B virus, for example, is never fully eliminated—even in those who have apparently cleared infection—and may reactivate during immunosuppression, e.g. with a B-cell depleting monoclonal antibody. CMV's low-level persistence contributes to the massive expansion of virus-directed CD8+ T cells seen in the elderly. In the case of HIV, targeting the low levels of virus which remain even in the face of highly suppressive anti-retroviral therapies remains an important therapeutic goal. Viral evolutionary capacity will remain a major challenge for the future: although the viruses illustrated are from diverse families, in each case viral evolution can contribute to persistence and pathogenesis. This is especially obvious in the cases of HIV and HCV, where high levels of viremia are accompanied by huge intra-host viral diversification—a result of the error-prone nature of RNA and retroviral replication. However, even relatively stable viruses such as CMV develop resistance to drugs in vivo and indeed we are only starting to scratch the surface of the diversity of these large DNA viruses, using next-generation sequencing. Viral diversity provides a major challenge for vaccines against viruses with variable envelopes and also for drug development. Once again, a ‘team’ approach, by targeting multiple pathways or sites within the virus should provide the key to effective vaccines and therapies. Developing a better understanding of these major virus infections requires attack from a variety of angles, including host genetics, viral genetics, cell biology, immunology and interventional clinical studies. The last decade has seen a massive transformation in the techniques used to study viral infections in man and a similar revolution in our understanding of pathogenesis. It is hoped that the next decade will produce similar advances in therapy and vaccines for these diverse and complex threats.