| Abstract | Knowledge of the correlates of viral escape from the cytotoxic T lymphocyte (CTL) response is needed for HIV-1 vaccine development. Mathematical models of this process have been constructed using deterministic equations, but the appearance of CTL escape mutants reported in the published data is not well approximated by deterministic models of viral escape. This finding motivated us to model viral escape as a stochastic process, with the aim of predicting parameter sets likely to prevent escape. Our model takes into account viral infection, mutation, CTL killing, and viral production and includes parameters for viral burst size, mutation rate, and probabilities of recognition and elimination by CTLs. We used the model to simulate viral production by both wild type and mutant strains in 50 to 500 individuals over 25 years. We found that our model reproduced the CTL escape phenomena seen in clinical data, with varying waiting times before the emergence of escape mutants. The model can be used to determine under what conditions we see escape frequencies like those observed in the data. We can also estimate the number of mutations needed for an escape mutant that arises after x years. Model results were consistent with a scenario in which mutant virus has a competitive advantage when CTL pressure against the wild type strain is strong, and when the number of infected cells is greater. In this way, a vaccine that stimulates a CTL response that incompletely eliminates wild type infected cells can promote escape by mutant virus. Such results may aid in the development of vaccines. |
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