Protective Effect of Val(129)-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met(129)) or valine (Val(129)) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met(129) homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val(129) Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met(129) Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val(129) Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val(129) Hu-PrP–positive humans with the emergence of new strain features.