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Letters to Nature
Nature 375, 606 - 611 (15 June 1995); doi:10.1038/375606a0

Antigenic oscillations and shifting immunodominance in HIV-1 infections

Martin A.  Nowak*, Robert M. May*, Rodney E. Phillips, Sarah Rowland-Jones, David G. Lalloo, Steven McAdam, Paul Klenerman, Britta Köppe, Karl Sigmund, Charles R. M. Bangham & Andrew J. McMichael

*Department of Zoology, University of Oxford, South Parks Road, 0X1 3PS, Oxford, UK
Molecular Immunology Group, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford 0X3 9DU, UK
Institut für Mathematik, Universität Wien, Strudlhofgasse 4, A-1090 Wien, Austria

ATYPICAL protein antigen contains several epitopes that can be recognized by cytotoxic T lymphocytes (CTL), but in a characteristic antiviral immune response in vivo, CTL recognize only a small number of these potential epitopes, sometimes only one1–2, this phenomenon is known as immunodominance1–10. Antigenic variation within CTL epitopes has been demonstrated for the human immunodeficiency virus HIV-1 (ref. 11) and other viruses12–7 and such 'antigenic escape' may be responsible for viral persistence. Here we develop a new mathematical model that deals with the interaction between CTL and multiple epitopes of a genetically variable pathogen, and show that the nonlinear competition among CTL responses against different epitopes can explain immunodominance. This model suggests that an antigenically homogeneous pathogen population tends to induce a dominant response against a single epitope, whereas a heterogeneous pathogen population can stimulate complicated fluctuating responses against multiple epitopes. Antigenic variation in the immunodominant epitope can shift responses to weaker epitopes and thereby reduce immuno-logical control of the pathogen population. These ideas are consistent with detailed longitudinal studies of CTL responses in HIV-1 infected patients. For vaccine design, the model suggests that the major response should be directed against conserved epitopes even if they are subdominant.

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