Complex Systems in Biology

Group Leader: Associate Professor Miles Davenport

---

Overview of Research

Although many acute infectious diseases are now effectively controlled by vaccination, we currently lack vaccines for many chronic infectious agents. These infections are of particular importance in the developing world, where hundreds of millions of people each year are affected by chronic infections such as HIV, tuberculosis and malaria. The Complex Systems in Biology group aims to understand the basic dynamics and pathogenesis of these infections, how the immune system interacts with them, and ultimately how we can control them. To achieve this we apply computational and mathematical approaches to understanding and predicting the complex interactions between host and pathogen. These interactions range from the molecular level (how immune molecules such as the T cell receptor interact with viral molecules), through to the dynamics of infection within individual hosts, and finally to the level of the host and pathogen population. The group brings together medical biologists, bioinformaticians, physicists, mathematicians, engineers and computer scientists to tackle these fundamental questions. The laboratory has a wide range of collaborations with experimentalists working in different areas of infection and immunity. A number of the major areas of research are outlined below.

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., Zaunders J.J., Hazenberg M.D., Schuitemaker H., and van Rij R.P. (2002) Cell turnover and cell tropism in HIV-1 infection. Trends in Microbiology, 10, 275-278

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., Chao, D. L. , and Perelson, A. S. (2004) Predicting the impact of a nonsterilizing vaccine against human immunodeficiency virus. Journal of Virology. 78:11340-51

Fernandez, C.S., Stratov, I., De Rose, R., Walsh, K., Dale, C.J., Smith, M.Z., Agy, M.B., Hu, S-L., Krebs, k., Watkins, D.I., O'Connor, D.H., Davenport, M.P., and Kent, S.J. (2005) Rapid viral escape at an immunodominant SHIV CTL epitope extracts a dramatic fitness cost. Journal of Virology 79: 5721-31

Davenport, M. P., Zhang, L., Shiver, J. W., Casimiro, D. R., Ribeiro, R. M., and Perelson, A. S. (2006) Influence of peak viral load on the extent of CD4+ T cell depletion in SHIV infection. Journal of Acquired Immune Deficiency Syndromes 41: 259-265

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

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

Venturi, V. Kedzierska, K, Turner, S.J., Doherty, P.C., and Davenport, M.P. (2007) Methods for comparing the diversity of samples of the T cell receptor repertoire. Journal of Immunological Methods 321, 182-195

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., Kedzierska, K., Tanaka, M.M., Turner, S.J., Doherty, P.C., and Davenport M.P. Method for assessing the similarity between subsets of the T cell receptor repertoire. Journal of Immunological Methods (2008) 329, 67-80

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

Melenhorst, J.J., Lay, M.D.H., Price, D.A., Adams, S.D., Zeilah, J., Sosa, E., Hensel, N.F., Follmann, D., Douek, D.C., Davenport, M.P., and Barrett, A.J. Contribution of the T cell receptor-b locus and HLA to the shape of the mature human Vb repertoire. (2008) Journal of Immunology 180. 6484- 6489

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
Davenport M.P., Fazou C., McMichael A.J. and Callan M.F.C. (2002) Clonal selection, clonal senescence and clonal succession: The evolution of the T cell response to infection with a persistent virus. Journal of Immunology, 168, 3309-3317

Crough, T.,. Burrows, J.M., Fazou, C., Walker, S., Davenport, M.P., and Khanna, R. (2005) Contemporaneous Fluctuations in T-cell Responses to Persistent Herpes Virus Infections. European Journal of Immunology 35: 139-149

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

Orr, Y., Wilson, D.P., Taylor, J.M., Bannon, P.G., Geczy, C., Davenport, M.P., Kritharides, L. (2007) A kinetic model of bone marrow neutrophil production which characterizes late phenotypic maturation. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 292, R1707-1716

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

Group Members

Funding Sources