CAD5-PrP-/- cells expressing HaPrP containing the D227E and R230S substitutions accumulated less PrPres following infection with BV.263K prions (Fig 5E), suggesting that decreased sequence identity between the C-terminal chimeric PrPC substrates and PrPSc in the inoculum is not sufficient to explain the observed effects, as BV.263K prions are more closely sequence matched to the D227E/R230S mutant than wild-type HaPrP. Here, PRNP is linked to infection.