scheme of passages of biological clone C-S8c1 in BHK-21 cells, in the presence or absence of mutagenic base and nucleotide analogues. Biological clones are depicted as filled squares and uncloned populations as empty circles. Thick arrows indicate high m.o.i. passages (1 to 5 PFU/cell). Drug concentrations during the infections are indicated on the corresponding arrows. A) The initial biological clone C-S8c1  was subjected to three parallel series of cytolytic infections, either in the presence of 5-fluorouracil (FU) or 5-azacytidine (AZC) or with no drug. B) C-S8c1 was subjected to 213 passages, and then MARLS clone was isolated as a mAb SD6 resistant mutant  (thin arrow). RA populations originated from serial cytolytic infections of MARLS in the presence of the indicated concentrations of ribavirin (R). The concentration of R was increased from 200 μM to 800 μM in the first 30 passages and from 800 μM to 5000 μM between passages 45 and 60. A bifurcation was established at passage 30 and the populations were subjected to 5 additional passages in the absence of R to yield the population RA0p35. CAp35 is the population obtained after 35 parallel passages of MARLS in the absence of drug.