We have openings for research scientists to work in our group at the Peter Medawar Building for Pathogen research, University of Oxford. The overarching aim of the work undertaken in the applicant?s research group is to better understand what are the CD8+ T cell responses mediating effective control of adult and paediatric HIV infection.

In a population-based study in KwaZulu-Natal, South Africa, we recently showed that only Gag-specific CD8+ T cell responses are associated with low viraemia in chronic infection. Env- or Accessory/Regulatory-specific responses are associated with high viral loads¹. The first aim of the proposed work is therefore to determine whether Gag-specific responses are inherently more effective than non-Gag-specific responses, or whether these discordant associations with viral load are merely the consequence of chronic infection.

The second aim is to determine whether HIV adaptation at an individual level is reflected by adaptation at a population level to these effective CD8+ T cell responses in Gag. Preliminary studies we have undertaken prompt the hypothesis that effective responses may persist at the population level even, as though virus adapts within individual subjects, because of fitness costs resulting from particular escape mutations^2-4. However, it is also clear that the virus can adapt to costly escape variants via the selection of compensatory mutations. We will be studying C-clade infected cohorts of HIV-infected persons in subSaharan Africa (including South Africa, Zambia, Botswana) and B-clade infected cohorts in UK and in the Caribbean.

The third aim is to extend studies initiated to examine whether CD8+ T cell response play an important role in control of paediatric HIV infection⁵. Our preliminary data suggest that they do, both via the specificity of the responses generated in infancy by the child⁶, and also via the impact maternal CD8+ T cell responses might have on both the specificity of the responses in the child⁷ and on the replicative capacity of transmitted virus.

1. Kiepiela, P. et al. CD8+ T cell responses to different HIV proteins have discordant associations with viral load. Nature Medicine, 2007, in press

2. Leslie, AJ, et al, Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA. Nature Medicine. 2004

3. Leslie, AJ, et al, Journal of Experimental Medicine, 2005

4. Martinez-Picado, J, Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. Journal of Virology, 2006

5. Prendergast A, et al, Paediatric HIV infection: global perspectives, progress and future challenges. Lancet, 2007, in press

6. Feeney, ME, et al, Immune escape precedes breakthrough HIV-1 viremia and broadening of the CTL response in a HLA-B27-positive long-term nonprogressing child, Journal of Virology, 2004

7. Goulder PJR, et al, Evolution and transmission of stable CTL escape mutants in HIV infection. Nature, 2001

Additional selected publications from our group:

• Goulder, PJR and Watkins DI. HIV and SIV CTL Escape: Implications for Vaccine design. Nature Reviews Immunology, 2004
• Kiepiela, P. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature, 2004

Professor Philip Goulder,

Peter Medawar Building for Pathogen Research,

South Parks Rd, Oxford OX1 3SY

Tel: +44-1865-281884

Fax: +44-1865-281236

Email: philip.goulder@ndm.ox.ac.uk