Principal areas of research Biography Research A number of immunologic and other host genetic differences, as well as viral and other factors account for the different outcomes, but it has emerged that the host T cell response plays an important part in prevention of long term infection. This is based on genetic associations with HLA genes, studies in model systems, and analysis of infected patients. The latter has the focus of the work in my lab. We initially studied patients with acute infection, although this is rarely encountered clinically. It is clear from such studies that those who go one to clear the virus typically mount –and sustain – broad T cell responses, both CD4 and CD8. These often target multiple epitopes and are maintained long after virus has been cleared from the blood. The situation in those who fail to clear virus is more complex – T cell responses (both CD4 and CD8) may either fail to emerge – or more commonly fail to be sustained and are typically hard to find in those with persistent infection (although they may be detected in increased frequencies in the liver). It appears 3 main factors emerge which may lead to failure of effective control. Virus variation is very important, leading to escape from antibodies and also T cells. A process of exhaustion of T cells may occur – this may result from a re-programming of T cells as they re-encounter antigen over time, and is associated with loss of function and number. Finally, regulation of T cells, particularly associated with Treg populations may occur. The liver during chronic infection is rich in FOXP3+ T cells. In order to prevent persistent infection with a vaccine, it is likely that broad and robust T cell responses (including CD8s) are needed. Emergence of such cells at an early stage could tip the kinetic balance in favour of the host such that escape, exhaustion and regulation – all of which are promoted by high virus loads and sustained replication – do not occur. Such a strategy has been shown to be effective in animal models. The role of T cells in chronic infection i.e. in determining long term clinical outcome also needs to be addressed. Certainly T cells can contribute to tissue damage as well as eliminating virus-infected cells. However, this is hard to disentangle and remains a goal for the future. A major clinical question is the impact of HIV, which both limits the T cell response in chronic infection and increases the rate of progression. Since about 1 in 10 HIV+ donors globally is HCV infected this is a substantial clinical issue as well as an immunological conundrum. Key Publications Klenerman P, Zinkernagel R (1998) Original antigenic sin impairs the CTL response against variant viruses. Nature.394 482-5. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD (2000) Analysis of Successful Immune Responses in Persons Infected with Hepatitis C Virus. J Exp Med 191: 1499-1512. Semmo N, Barnes E, Taylor C, Kurtz J, Harcourt G, Smith N, Klenerman P (2005) T-cell responses and previous exposure to hepatitis C virus in indeterminate blood donors. Lancet 365: 327-329. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, Robbins GK, Casson DR, Reiser M, Dusheiko G, Allen TM, Chung RT, Walker BD, Klenerman P (2004) High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 127: 924-936. Review: Klenerman P, Hill A (2005) T cells and viral persistence: lessons from diverse infections. Nat Immunol 6: 873-879. |
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