Complex Systems in Biology Group - Research Projects and Key Publications
HIV Infection and Immunity
HIV infects predominantly CD4 ‘helper’ T cells during infection, leading to their destruction. The loss of these helper T cells in turn cripples the immune response to the virus by other arms of the immune system including antibodies and killer T cells. In addition, the very high mutation rate of the virus means that it can often ‘escape’ immune recognition. We aim to understand this complex interaction of a number of levels:
- Studying the dynamics of the immune response, and its impact on virus.
- Understanding the dynamics of infection and death of the CD4 T cells infected by the virus.
- Measuring the rate of viral mutation and selection as it escapes from the host immune response.
Key publications
Davenport, M.P., Ribeiro, R.M. and A. S. Perelson. (2004) Kinetics of virus specific CD8+ T cells and the control of HIV infection.
Journal of Virology. 78:10096-10103
Davenport, M.P., Ribeiro, R.M., Zhang, L., Wilson, D.P., Perelson, A.S. (2007) Understanding the mechanisms and limitations of immune control of HIV.
Immunological Reviews 216, 164-175
Loh, L., Petravic, J., Batten, C.J., Davenport, M.P., Kent, S.J. (2008) Vaccination and timing influence SIV immune escape viral dynamics
in vivo. PLoS Pathogens 4(1) E12
Petravic, J., Loh, L., Kent, S.J., and Davenport, M.P. CD4+ Target cell availability determines the dynamics of immune escape and reversion in vivo. (2008)
Journal of Virology. 82, 4091-4101
Davenport, M.P., Loh, L., Petravic, J., Kent, S.J., (2008) Rates of HIV immune escape and reversion: Implications for vaccination.
Trends in Microbiology. 16. 561-566
Venturi, V., Chin, H.Y., Asher, T.E., Ladell, K., Scheinberg, P., Bornstein, E., van Bockel, D., Kelleher
§, A.D., Douek, D.C., Price, D.A., and Davenport, M.P. (2008) TCR b-chain sharing in human CD8
+ T cell responses to cytomegalovirus and EBV.
Journal of Immunology. 181, pp7853-7862
Lay, M.D.H., Petravic, J., Gordon, S.N., Engram, J., Silvestri, G., and Davenport, M.P. (2009) Is gut the major source of virus in early SIV infection?
Journal of Virology. 83, 7517
Schlub, T., Smyth, R.P., Grimm, A., Mak J., Davenport, M.P. Measuring recombination between closely related HIV-1 genomes.
PLoS Computational Biology. 6(4) e100766
The role of the T cell Receptor Repertoire in Immune Responses
CD8 “killer” T cells are important in the control of many chronic infections, and most viruses are recognized by a diverse ‘repertoire’ of different T cells in the host. Some agents such as HIV are able to rapidly mutate to ‘escape’ immune recognition. The ‘diversity’ or ‘specificity’ of the repertoire of T cells recognizing the virus is thought to be an important determinant of how easily the virus can escape recognition. The recognition of a variety of viral peptides is made possible by a large diversity of T cell receptors (TCRs) that are expressed on the surface of the T cells. These TCRs are produced in the thymus by a process of gene recombination. Thus we aim to:
- Develop statistical tools to allow the comparison of repertoires to address underlying questions in infection. For example; “how does vaccination change the repertoire?”, or “how is diversity correlated with immune escape?”.
- Understand the processes that ‘shape’ the T cell repertoire (eg. thymic production; thymic, peripheral, and antigen selection; age) and the role that the diverse TCR repertoire plays in immune responses.
Key publications
Venturi, V., Kedzierska, K, Price, D.A., Turner, S.J., Doherty, P.C., Douek, D.C., and Davenport, M.P. (2006) Sharing of T cell receptors in antigen specific responses is driven by convergent recombination. Proceedings of the National Academy of Sciences (USA) 103, 18691-18696
Davenport, M.P., Price, D.A., McMichael, A.J. (2007) The T cell repertoire in infection and vaccination: Implications for the control of persistent infection.
Current Opinion in Immunology 19, 294-300
Venturi, V., Price, D. A., Douek, D., and Davenport, M.P. The molecular basis for public T cell responses. (2008)
Nature Reviews Immunology. 8, 231- 238
Venturi, V., Chin, H.Y., Price, D.A., Douek, D.C., and Davenport, M.P. (2008) The role of production frequency in the sharing of SIV specific CD8
+ T cell receptors between macaques.
Journal of Immunology. 181, 2597-2609
Venturi, V., Chin, H.Y., Asher, T.E., Ladell, K., Scheinberg, P., Bornstein, E., van Bockel, D., Kelleher
§, A.D., Douek, D.C., Price, D.A., and Davenport, M.P. (2008) TCR b-chain sharing in human CD8
+ T cell responses to cytomegalovirus and EBV.
Journal of Immunology. 181, pp7853-7862
Greenaway, H.Y., Kurniawan, M., Price, D.A., Douek, D.C., Davenport, M.P. and Venturi, V. (2009) Extraction and characterization of the rhesus macaque T cell receptor b-chain genes.
Immunology and Cell Biology 87, 546
Kedzierska, K., Valkenburg, S.A., Guillonneau, C., Hubert, F-X., Cukalac. T.,
Curtis, J.M., Stambas, J., Scott, H.S., Kedzierski, L., Venturi, V., Davenport, M.P. (2010) Diversity and clonotypic composition of influenza-specific CD8
+ TCR repertoires remain unaltered in the absence of Aire.
European Journal of Immunology. 40, 1-11
Rudd, B.D., Venturi, V., Smithey, M.J., Way, S.S., Davenport, M.P., and Nikolich-Zugich, J. Diversity of the CD8+ T Cell Repertoire Elicited against an Immunodominant Epitope Does Not Depend on the Context of Infection.
Journal of Immunology
Dynamics of Infection and Immunity
Infection and immunity involves a dynamic interaction between pathogen growth and the development of the host cell response. Traditional approaches tend to consider these interactions ‘cross-sectionally’ (ie: comparing peak viral levels and peak immune response). However, the timing and rate of immune activation may sometime be a crucial determinant of outcome. For example, a delay in the killer T cell response to HIV infection seems one reason for the inability of vaccines to mediate control of infection. We are studying the dynamics of infection in different systems such as HIV infection of monkeys, influenza and malaria infection of mice, and a number of chronic viral infection of humans. We believe that comparative studies of host-pathogen interactions in different infections will elucidate the basic’ rules of engagement’ between host and pathogen that determines the outcome of infection.
Key publications
Cromer, D., Evans, K.J, Schofield, L., Davenport, M.P. (2006) Preferential invasion of reticulocytes during late-stage Plasmodium berghei infection accounts for reduced circulating reticulocyte levels.
International Journal for Parasitology 36: 1389-1397
Davenport, M.P., Ribeiro, R.M., Zhang, L., Wilson, D.P., Perelson, A.S. (2007) Understanding the mechanisms and limitations of immune control of HIV.
Immunological Reviews 216, 164-175
Belz, G.T., Zhang, L., Lay, M., Kupresanin, F., and Davenport, M.P. (2007) Killer T cells regulate antigen presentation for early expansion of memory, but not naïve, CD8+ T cells.
Proceedings of the National Academy of Sciences (USA) 104, 6341-6346
Schlub, T.E., Venturi, V., Kedzierska, K., Wellard, C., Doherty, P.C., Turner, S.J., Ribeiro, R.M., Hodgkin, P.D., Davenport, M.P., (2009) Division-linked differentiation can account for CD8
+ T cell phenotype in vivo.
European Journal of Immunology. 39, 67-77
Davenport, M.P., Belz, G.T., Ribeiro, R.M. (2009) The race between infection and immunity – How do pathogens set the pace?
Trends in Immunology. 30, 61-66
Schlub, T.E., Badovinac, V.P, Sabel, J.T., Harty, J.T., Davenport, M.P. (2010) Predicting the expression of CD62L during the CD8+ T cell response in vivo.
Immunology and Cell Biology. 88, 157