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Principal areas of research
HIV therapeutic vaccines, HIV immunology
Biography
Lucy Dorrell obtained a Bachelor of Medicine from the University of Southampton in 1988. After junior hospital posts during which she obtained MRCP, she began her research career in 1993 as a Clinical Research Fellow in Communicable Diseases and Genitourinary Medicine at Imperial College, London with Professor Jonathan Weber. She was awarded a DM degree in 1998 from the University of Southampton for her research into antigen-presenting cell function in HIV infection. She was subsequently awarded an MRC Clinical Training Fellowship to study immunological mechanisms of resistance to HIV-1 and HIV-2 under Professor Sarah Rowland-Jones at MRC Laboratories, The Gambia and at the Weatherall Institute of Molecular Medicine. In 2000 she was awarded an MRC Clinician Scientist Fellowship, which she took up in 2002 after completing clinical specialist training and obtaining a CCST in HIV/GUM. With Professor Andrew McMichael she set up a programme of translational research evaluating therapeutic immunisation in HIV-1 infection with novel DNA and modified vaccinia virus Ankara-vectored HIV-1 vaccines developed at MRC Human Immunology Unit. She was awarded a HEFCE Clinical Senior Lectureship in 2007. Her research team is conducting further clinical therapeutic vaccination studies while also investigating mechanisms which determine success or failure of host immune control of HIV.
Research
The global burden of HIV-1 infections is enormous and the majority of infected people do not have access to effective drug treatment. Virus-specific CD8+ T cell responses control HIV-1 replication to a variable degree and are a key determinant of the rate at which an infected person progresses to AIDS. CD8+ T cell responses wane after effective antiretroviral therapy (ART) is initiated and do not recover quickly enough to prevent viral rebound if treatment is stopped. There is therefore a strong rationale for using therapeutic vaccination during ART as a means to boost HIV-1-specific CD8+ T cell responses, with the goal of achieving better immune control of HIV-1 and safe withdrawal of drug treatment. Stabilisation of CD4 counts for sustained periods after withdrawal of HAART would significantly reduce the cost and long-term toxicity of antiretroviral therapy. Simian models of AIDS virus infections indicate that short-term control of virus replication following vaccination is feasible.
We have set up a translational research programme at MRC Human Immunology Unit (MRC HIU), Weatherall Institute of Molecular Medicine (WIMM) which aims to develop immunotherapy for HIV-1 infection as an adjunct to combination antiretroviral therapy (HAART). We have shown that a novel viral-vectored HIV-1 vaccine candidate, ‘MVA.HIVA’, when delivered by intradermal injection, is safe in HIV-1-infected HAART-treated patients and can significantly augment virus-specific cellular immune responses. Immune modulation, indicated by changes in the breadth and hierarchy of viral epitopes targeted, was also evident. Viral variants which can evade CD8+ T cell recognition frequently emerge under immune selective pressure; 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.
Accumulating data suggest that poxvirus-vectored vaccines may need to be combined with other immuno-modulatory strategies in order to impact significantly on viral rebound during short-term antiretroviral therapy interruptions. The next step is therefore to maximise immunogenicity, first by combining MVA.HIVA with a complementary vaccine, ‘MVA.RENTA’: together, these should stimulate cellular responses to proteins encoded by six of the nine HIV-1 genes. In the longer term, we plan to include MVA.HIVA/RENTA in heterologous vaccination regimens with other viral-vectored vaccines in order to achieve a 5-10-fold boost in the levels of HIV-1-specific T cells.
We have also conducted a pilot study involving supervised antiretroviral therapy interruption: by tracking the evolution of adaptive CD8+ T cell responses to the virus we have demonstrated that the cellular immune response to HIV is too weak and too slow to prevent viral rebound after drug withdrawal. This may be a key factor contributing to the failure of CD8+ T cell responses to control virus replication. We are currently investigating the mechanisms underlying these observations.
Key Publications
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.
B Ondondo, H Yang, T Dong, K de Gleria, N Goonetilleke, N Winstone, C Conlon, S Rowland-Jones, T Hanke, A McMichael & L Dorrell.
Immunisation with recombinant modified vaccinia virus Ankara expressing HIV-1 gag in HIV-1-infected subjects stimulates broad functional CD4+ T cell responses. Eur J Immunol. 2006 ;36:2585-94.
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.
R Sutherland, H Yang, T Scriba, B Ondondo, C Conlon, S Fidler, A Suttill, H McShane, R Phillips, A McMichael, L Dorrell.
Persistent impairment of IFN--secreting capacity in mycobacterial antigen-specific CD4 T cells during chronic HIV-1 infection despite long term HAART. AIDS 2006; 20: 821-9.
L. Dorrell, H Yang, AK Iversen, CP Conlon, A Suttill, M Lancaster, T Dong, I Cebere, A Edwards, S Rowland-Jones, T Hanke, AJ McMichael.
Therapeutic immunisation of HAART-treated HIV-1-infected subjects: safety and immunogenicity of an HIV-1 gag / poly-epitope DNA vaccine. AIDS 2005, 19: 1321-3
L Dorrell.
Therapeutic immunization strategies for the control of HIV-1. Expert Rev Vaccines. 2005;4:513-20.
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