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SUMMARY:What constitutes a protective HLA class I molecule\, and why doesn
 't it always work? - Dr Becca Asquith\, Imperial College London
DTSTART:20110316T123000Z
DTEND:20110316T133000Z
UID:TALK28711@talks.cam.ac.uk
CONTACT:Sue Griffin
DESCRIPTION:Abstract:\n\nTwo individuals\, infected with an identical path
 ogen can have very different clinical outcomes. One determining factor is 
 HLA class I genotype: different HLA class I alleles have been associated w
 ith significant protective or detrimental effects. However\, the protectiv
 e and detrimental HLA molecules do not always “work”\; i.e. we see inc
 omplete penetrance of the protective and detrimental traits. I will presen
 t our work to understand what makes an HLA class I molecule protective or 
 detrimental and why these effects are not seen consistently for all cohort
 s.\n\nResearch Interests\n\nWhat constitutes an effective CD8+ T cell resp
 onse? And does CD8+ T cell efficacy determine human health? We aim to answ
 er these questions with the long term goal of a deterministic\, predictive
  model to guide the manipulation of adaptive immunity to alleviate human d
 isease. We are working to develop\, validate and apply the approaches nece
 ssary to achieve this goal. There are 3 key areas to be tackled: we need t
 o quantify CD8+ T cell efficacy\, identify the determinants of CD8+ T cell
  efficacy and assess the in vivo relevance of CD8+ T cells.\n\n(i) Quantif
 ying CD8+ T cell efficiency \n\nOur work to quantify CD8+ T cell efficacy 
 includes the development of novel techniques to measure the strength of th
 e CD8+ T cell response in HIV-1\, SIV-1 and HTLV-I infections1-3. This pro
 vided the first quantitative insight into the strength of the human HIV-sp
 ecific CD8+ T cell response in vivo. We showed that the majority of infect
 ed cell death cannot be attributed to CD8+ T cells. We also demonstrated t
 hat CD8+ T cell killing is more efficient in SIV-infected macaques than HI
 V-infected humans. This indicates that the macaque model may be an over-op
 timistic model of CD8+ T cell control with important consequences for the 
 interpretation of HIV vaccine studies which are routinely conducted in mac
 aques. These techniques have been widely used by ourselves and others and 
 have been adopted by the National Centre for Human Retrovirology as clinic
 al trial endpoints.\n\n(ii) What determines the efficiency of the CD8+ T c
 ell response?\n\nTo investigate the determinants of CD8+ T cell efficiency
  we developed an innovative approach that integrates improved methods for 
 epitope prediction4  with experimental data and cohort analysis. This reso
 urce is available online. Application of this method has enabled us to ide
 ntify the constituents of a protective CD8+ T cell response to HTLV-I infe
 ction5. Extending this approach to HCV led us to find an unanticipated\, e
 nhancing role for KIR2DL2 in adaptive immunity.\n\n(iii) Investigating the
  in vivo relevance of CD8+ T cells\n\nOne of the most contentious question
 s in the field is “how important is the CD8+ T cell response”\; i.e. d
 oes it really matter to an individual if their CD8+ T cell response is fun
 ctioning efficiently or not. Here we have quantified T cell turnover in vi
 vo in HTLV-I infected patients6\, estimated the impact on HIV viral load o
 f viral escape from the CTL response7 and quantified the relative importan
 ce of CD8+ T cells\, B cells and NK cells in determining the course of acu
 te viremia in primary SIV infection.\nWe also work extensively on models t
 o assess the relationship between lymphocyte dynamics and disease\, such a
 s the disregulation of B cell kinetics in patients with chronic lymphocyti
 c leukaemia6\, 8-11. This included development and application of models o
 f deuterated glucose\, BrdU and CFSE labelling.\n
LOCATION:Lecture Theatre\, Department of Pathology\, Tennis Court Road
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