Group Leader: Miles Davenport

Overview:

The Complex Systems in Biology group utilises theoretical, mathematical, computer modelling and bioinformatics approaches to increase our understanding of biology. Biological processes occur at the molecular, cellular, and population level. The combination of analysis of experimental data and computer modelling allow integration of our understanding of these different levels, and provide insights into the complexities of biological processes.

Projects:

Immune responses to HIV:
HIV infection is characterized by an acute illness, followed by a long period of 'latency' and later immunodeficiency and AIDS. The primary target for viral infection is the "helper" (CD4) T cell. "Killer" (CD8) T cells are thought to control the virus during the long latent period of infection. Immunological control may ultimately be lost due to killer T cell 'exhaustion", viral mutation, or viral killing of "helper" T cells. Modelling provides an opportunity to gain insights into the role of the immune system both in the control of HIV and as a target of viral infection. Such understanding is key to rational design of vaccines to prevent or control HIV infection.

Viral evolution in HIV:
HIV enters its target cells through binding to CD4 molecules and chemokine receptor molecules on the surface of target cells. Early infection with HIV is dominated by virus that binds to the CCR5 chemokine receptor. Later in infection, the virus often mutates so that it can bind to the CXCR4 chemokine receptor. This mutation is often accompanied by rapid disease progression. Modelling of viral infection and T cell replication rates suggest that the more virulent virus targeting CXCR4 evolves due to increases in the proliferation rate of T cells. New antiretroviral drugs are being developed that target chemokine receptors to prevent HIV entry into cells. Understanding of the evolution of viral phenotype allows prediction of the likely outcome of these new therapies.

Immunological memory:
Infection or vaccination leads to a rapid increase in the number of immune cells able to control a pathogen. Following infection, many of these cells die, but a small population of 'memory' cells persists for many years. If the host is infected a second time, the immune system delivers a faster and more potent response. We currently understand little about why some cells become memory cells, the factors that affect the survival of memory cells, and the differences between the responses to an initial versus a second infection. Modelling of immune responses allows insight into the dynamics of 'memory' generation and responses.

T cell repertoire:
T cells play an important role in immune responses to viral infections. The recognition of a variety of viral peptides is made possible by a large diversity of T cell receptors that are produced in the thymus by a process of random recombination of gene segments. Investigation of the T cell repertoire using bioinformatics, computational and statistical analysis provides insight into the processes that determine the diversity of the T cell repertoire and the role of the diversity of the T cell repertoire in immune responses to infectious diseases. Such insight is important for the treatment of, and vaccination against, infectious disease.

Understanding the dynamics of antigen presentation in vivo:
Antigen presentation within lymph nodes is crucial for initiation of CD8+ T cell responses following viral infection. The duration of presentation may affect both the magnitude and the quality of the response. We are investigating the dynamics of antigen presentation in vivo following infection with mathematical modelling and statistical analysis of experimental data. In this way we are able to gain an understanding of the factors that determine the timing, magnitude and duration of antigen presentation, which is important for understanding the dynamics of the immune response.

Further Information About Complex Systems in Biology group research:
http://www.jsmf.org/grants/cs/essays/2002/davenport.htm

Group Members:

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

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

Zhang, L., Ribeiro, R.M., Mascola, J.R., Lewis, M.G., Steigler, G., Katinger, H., Perelson, A.S., Davenport, M.P. (2004) Effects of antibody on viral kinetics in SHIV infection: Implications for vaccination. Journal of Virology, 78:5520-5522

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

Kent, S.J., Fernandez, C.S., Dale, C.J., and Davenport, M.P. (2005) Reversion of immune escape HIV variants upon transmission: insights into effective viral immunity. Trends in Microbiology 13: 243-246

Davenport, M. P., Zhang, L., Bagchi, A., Fridman, A., Fu, T. M., Schleif, W. A., Shiver, J. W., Ribeiro, R. M., and A. S. Perelson. (2005). High potency HIV vaccination leads to delayed and reduced CD8+ T cell expansion, but nevertheless improved viral control. Journal of Virology, 79: 10059-10062

Kedzierska, K., La Gruta, N., Davenport, M.P., Turner, S.J., and Doherty, P.C. (2005) Contribution of T cell receptor affinity to the overall avidity in virus-specific CD8+ T cell responses. Proceedings of the National Academy of Sciences (USA) 102: 11432-11437

Ribeiro, R.M., Hazenberg, M.D. Perelson, A.S., and Davenport, M.P. (2006) Naïve and memory cell turnover as drivers of CCR5 to CXCR4 tropism switch in HIV-1: implications for therapy. Journal of Virology 80: 802-809

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

Kedzierska, K., Venturi, V., Field, K., Davenport, M.P., Turner, S.J., and Doherty, P.C. (2006) Early establishment of diverse T cell receptor profile for influenza specific CD8+ CD62Lhi memory cells. Proceedings of the National Academy of Sciences (USA) 103: 9184-9189

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 of Parasitology 36: 1389-97

Venturi, V., Kedzierska, K, Price, D.A., Turner, S.J., Doherty, P.C., Douek, D.C., and Davenport, M.P. Sharing of T cell receptors in antigen specific responses is driven by convergent recombination. Proceedings of the National Academy of Sciences (USA) 103:18691-6.

Venturi V., Kedzierska K., Turner S.J., Doherty P.C., Davenport M.P. (2007) Methods for comparing the diversity of samples of the T cell receptor repertoire. Journal of Immunological Methods 321:182-95.

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.

Fernandez, C.S., Smith, M.Z., Batten, C.J., de Rose, R., Reece, J.C., Rollman, E., Venturi, V., Davenport, M.P., and Kent, S.J. (2007)Vaccine-induced T cells control reversion of AIDS virus immune escape mutants. Journal of Virology 81: 4137-4144.

Belz, G.T., Zhang, L., Lay, M., Kupresanin, F., and Davenport, M.P. 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.

Loh, L., Batten, C.J., Janka Petravic, P., Davenport, M.P., Kent, S.J., In vivo fitness costs of different Gag CD8 T cell escape mutant simian-human immunodeficiency viruses in macaques. Journal of Virology 81: 5418-5422.

Davenport, M.P., Price, D.A., McMichael, A.J. The T cell repertoire in infection and vaccination: Implications for the control of persistent infection. Current Opinion in Immunology 19: 294-300.

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.

Wilson, D.P., Mattapallil, J.J., Lay, M., Zhang, L., Roederer, M., Davenport, M.P. (2007) Estimating the infectivity of CCR5-tropic SIVmac251 in the gut. Journal of Virology 81, 8025-8029.

Funding Sources:

James S. McDonnell Foundation 21st Century Research Awards/Studying Complex Systems

Sylvia and Charles Viertel Senior Medical Research Fellowship

NH&MRC Project Grant

ARC

National Institutes of Health (USA)