Prof Paul Klenerman
Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY
+44 (0)1865 281885
Principal areas of research
T cell responses to persistent viruses, especially hepatitis C virus (HCV).
I trained in medicine in Cambridge and then Oxford, and specialised in infectious diseases. My PhD was with Rodney Phillips and Andrew McMichael in Oxford, on T cell responses to HIV, especially looking at the influence of escape mutants. I did a postdoc with Rolf Zinkenagel and Hans Hengartner in Zurich, looking at virus persistence in the LCMV model. Subsequently I returned to Oxford and since 1999 have been analysing immune responses to hepatitis C virus. The lab also runs projects using the new tools which became available recently, to analyse immune responses to CMV, parvoviruses B19 and PARV4 and HIV. My work has been funded largely through the Wellcome Trust since 1992, most recently with a senior fellowship.
Hepatitis C virus infects around 170 million people globally and is a major cause of liver disease, including liver cancer. No vaccine currently exists, and the current treatment is only partially effective, as well as being expensive and associated with substantial side effects. About a quarter of those initially infected clear the virus spontaneously, although the majority become persistently infected. The aim of much of the research is to try and understand the key differences between host responses which lead to a successful outcome (clearance) as opposed to a unsuccessful outcome (persistence).
Clearance vs. persistence
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.
The role of 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 (see HCV vaccines page).
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. We are focusing currently on the specific role of CD161+ T cells in the liver – this a group of T cells with distinct homing and function, including expression of RORgt and IL-17, which may play a role in early and long term outcome.
The impact of HIV
Finally, 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.
Klenerman P, Rowland-Jones S, McAdam S, Edwards J, Daenke S, Lalloo D, Koppe B, Rosenberg W, Boyd D, Edwards A, et al. (1994) Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature 369: 403-407.
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.
John W. Northfield, Victoria Kasprowicz, Michaela Lucas, Nadine Kersting, Bertram Bengsh, Arthur Kim, Rodney E. Phillips, Bruce D. Walker, Robert Thimme, Georg Lauer, Paul Klenerman (2008) CD161 expression on hepatitis C virus-specific CD8+ T cells suggests a distinct pathway of T cell differentiation. Hepatology 47(2):396-406.
Eva Billerbeck, Yu-Hoi Kang, Lucy Walker, Helen Lockstone, Stefanie Grafmueller, Vicki Fleming,
Jonathan Flint, Chris B. Willberg, Bertram Bengsch, Bianca Seigel, Narayan Ramamurthy, Nicole Zitzmann, Eleanor J. Barnes, Jonarthan Thevanayagam, Anisha Bhagwanani, Alasdair Leslie, Ye H. Oo, Simon Kollnberger, Paul Bowness, Oliver Drognitz, David H. Adams, Hubert E. Blum, Robert Thimme, and Paul Klenerman (2010) Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A 16;107(7):3006-11.
Review: Klenerman P, Hill A (2005) T cells and viral persistence: lessons from diverse infections. Nat Immunol 6: 873-879.