Dr Lucy Dorrell
| Address: | Weatherall Institute of Molecular Medicine |
| Tel: | +44 (0)1865 222 145 |
| Email: | |
| Website: | HIV Vaccine Programme / External webpage |
Principal areas of research HIV therapeutic vaccines, HIV immunology |
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Biography
I am a Senior Clinical Lecturer in Genitourinary / HIV Medicine. I trained in Medicine at the University of Southampton and began research in HIV infection at Imperial College London, moving to Oxford University after award of a DM degree. I spent two years at MRC Laboratories, The Gambia studying immunity to HIV-1/HIV-2 in exposed uninfected individuals. I completed specialist clinical training in Oxford and took up a Clinician Scientist Fellowship in 2002, during which I conducted a series of trials to investigate the potential of therapeutic DNA and viral-vectored HIV-1 vaccines to augment CD8+ T cell responses against HIV-1 in collaboration with Dr Tomas Hanke and Professor Andrew McMichael (MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine). This has led to a translational research programme funded by MRC and Oxford NIHR Biomedical Research Centre, which focuses on therapeutic immunomodulation through the induction of broad and potent HIV-specific CD8+ T cells responses.
Research
Combination antiretroviral therapy (ART) is an undoubted success, yet the majority of HIV-1-infected individuals living in high prevalence areas are unable to access effective antiretroviral therapy. Current drug regimens are not curative and must be continued for life, which means patients may be exposed to antiretroviral agents for several decades. A major aim of our research is to develop strategies to enable patients to achieve a ‘functional cure’, which would enable them to stop ART safely while maintaining excellent control of HIV-1.
Since virus-specific CD8+ T cell responses are a key determinant of the rate of progession to AIDS, we are investigating the capacity of new vaccine candidates to boost and / or improve the functional capacity of CD8+ T cells in HIV-1-infected individuals by vaccination during ART. Viral variation is a major obstacle to the development of an effective HIV-1 vaccine. However, as some escape mutations impair viral fitness, therapeutic vaccination may be exploited to target CD8+ T cell responses to more vulnerable regions of the viral proteome. We are currently conducting clinical trials of a novel HIV-1 immunogen, HIVconsv, which comprises sequences representing the most highly conserved regions of the viral genome. HIVconsv is expressed in various DNA and attenuated viral vectors and delivered in heterologous boost regimens. Our long-term goal is to achieve drug-free remission in HIV-1 infection by deploying potent therapeutic vaccines in combination with antiretroviral drugs and agents to target latently infected T cells.
In parallel, we are studying potential immune correlates of HIV-1 control. The antiviral inhibitory activity of CD8+ T cells in vitro may provide a better measure of a protective immune response than widely used cytokine-based assays. We have shown that CD8+ T cell antiviral activity is a strong predictor of CD4+ cell decline in observational studies, which suggests it might be a useful benchmark for vaccine immunogenicity in phase I/II clinical trials. In addition, we have developed tools to enable us to dissect the mechanisms of viral inhibition by CD8+ T cells.
Key Publications
Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, Yan H, Huang X, Angus B, Kuldanek K, Fidler S, Denny TN, Birks J, McMichael AM, Dorrell L. The antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ cell decline in HIV-1 infection. J Infect Dis 2012, in press.
Howles S, Guimarães-Walker A, Yang H, Hancock G, di Gleria K, Tarragona-Fiol T, Hayes P, Gilmour J, Bridgeman A, Hanke T, McMichael A, Dorrell L. Vaccination with a modified vaccinia virus Ankara (MVA)-vectored HIV-1 immunogen induces modest vector-specific T cell responses in human subjects. Vaccine 2010;28:7306.
Murphy RL, Autran B, Katlama C, Brucker G, Debre P, Calvez V, Clotet B, Clumeck N, Costagliola D, Deeks SG, Dorrell L, Gatell J, Haase A, Klein M, Lazzarin A, McMichael AJ, Papagno L, Schacker TW, Wain-Hobson S, Walker BD, Youle M.
A step ahead on the HIV collaboratory. Science. 2009;324(5932):1264-5.
H Yang, T Dong, E Turnbull, S Ranasinghe, B Ondondo, N Goonetilleke, N Winstone, K di Gleria, C Conlon, P Borrow, T Hanke, A McMichael & L Dorrell. Broad TCR usage in functional HIV-1-specific CD8+ T cell expansions driven by vaccination during highly active antiretroviral therapy. J Immunol. 2007;179:597-606.
L Dorrell, H Yang, B Ondondo, T Dong, K di Gleria, A Suttill, C Conlon, D Brown, P Williams, P Bowness, N Goonetilleke, T Rostron, S Rowland-Jones, T Hanke & A McMichael. Expansion and diversification of virus-specific T cells following immunisation of HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara / HIV-1 gag vaccine. J Virol 2006; 80: 4705-4716.
