ANTIGENIC OSCILLATIONS AND SHIFTING IMMUNODOMINANCE IN HIV-1 INFECTIONS

A TYPICAL protein antigen contains several epitopes that can be recogn ized by cytotoxic T lymphocytes (CTL), but in a characteristic antivir al immune response in vivo, CTL recognize only a small number of these potential epitopes, sometimes only one(1,2), this phenomenon is known as immunodominance(1-10). Antigenic variation within CTL epitopes has been demonstrated for the human immunodeficiency virus HIV-1 (ref. 11 ) and other viruses(12-17) and such 'antigenic escape' may be responsi ble for viral persistence. Here we develop a new mathematical model th at deals with the interaction between CTL and multiple epitopes of a g enetically variable pathogen, acid show that the nonlinear competition among CTL responses against different epitopes can explain immunodomi nance. This model suggests that an antigenically homogeneous pathogen population tends to induce a dominant response against a single epitop e, whereas a heterogeneous pathogen population can stimulate complicat ed fluctuating responses against multiple epitopes. Antigenic variatio n in the immunodominant epitope can shift responses to weaker epitopes and thereby reduce immunological control of the pathogen population. These ideas are consistent with detailed longitudinal studies of CTL r esponses in HIV-1 infected patients. For vaccine design, the model sug gests that the major response should be directed against conserved epi topes even if they are subdominant.