CLINICAL-DATA SETS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE TRANSCRIPTASE-RESISTANT MUTANTS EXPLAINED BY A MATHEMATICAL-MODEL

Treatment of human immunodeficiency virus type 1 (HIV-1) infection dur ing the clinical latency phase with drugs inhibiting reverse transcrip tase (RT) reduces the HIV-1 RNA load and increases the CD4(+) T-cell c ount, Typically, however, the virus evolves mutations in the RT gene t hat circumvent the drugs. We develop a mathematical model for this sit uation, The model distinguishes quiescent from activated CD4(+) T cell s, incorporates the fact that only activated cells can become producti vely infected by HIV-1, embodies empirical estimates for the drug resi stance and the mutation frequency for each of the HIV-1 drug-resistant mutants, and assumes the antiviral immune response to remain constant over the course of the experiments, We analyze clinical data on the e volution of drug-resistant mutants for the RT inhibitors lamivudine an d zidovudine, The results show that the evolutionary sequence of the d rug-resistant mutants in both data sets is accounted for by our model, given that lamivudine is more effective than zidovudine, Thus, curren t empirical estimates of the mutation frequencies and the drug resista nces of the mutants suffice for explaining the data, We derive a criti cal treatment level below which the wild-type HIV-1 RNA load can rebou nd before the first drug-resistant mutant appears, Our zidovudine data confirm this to be the case, Thus, we demonstrate in the model and th e data that the rebound of the HIV-1 RNA load in the case of zidovudin e is due to the outgrowth of wild-type virus and the first drug-resist ant mutant, whereas that in the case of lamivudine can only be due to the drug-resistant mutants, The evolution of drug resistance proceeds slower in the case of zidovudine because (i) zidovudine is not as effe ctive as lamivudine and (ii) the first zidovudine drug-resistant mutan t is competing with the rebounding wild-type virus.