No abstract

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD), two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asn178) of the prion protein gene. The possibility that a second genetic component modified the phenotypic expression of the Asn178 mutation was investigated. FFI and the familial CJD subtype segregated with different genotypes determined by the Asn178 mutation and the methionine-valine polymorphism at codon 129. The Met129, Asn178 allele segregated with FFI in all 15 affected members of five kindreds whereas the Val129, Asn178 allele segregated with the familial CJD subtype in all 15 affected members of six kindreds. Thus, two distinct disease phenotypes linked to a single pathogenic mutation can be determined by a common polymorphism.

Chimpanzees are susceptible to infection by di- No antibodies to the carboxyl terminus of HTLV-IUB gpl20 were observed in sera of chimpanzees inoculated with HTLV-ITIRF or with the brain-tissue strain, and those sera did not neutralize HTLV-IIIB. A rabbit immunized with the C-terminal portion of gpl20 acquired neutralizing antibodies that bound to four domains of the HTLV-UIB external envelope as analyzed by reactivity to 536 overlapping nonapeptides of gpl20. One of these domains in the variable region V3, with the amino acid sequence IRIQRGPGRAFVTIG (amino acids 307-321), bound to all chimpanzee sera that neutralized HTLV-IIIB but not to the serum of the HTLV-IUIRF-inoculated chimpanzee that did not neutralize HTLV-UIB. The HTLV-IIIRF sequence at the same location, ITKGPGRVIYA, was recognized by the serum of the HTLV-UIERF-inoculated chimpanzee but not by any sera of the HTLV-IUB-inoculated or LAV-i-inoculated chimpanzees. The HTLV-UIB residues RIQR and AFV and the HTLV-IIRF residues lysine and VIYA, flanking a highly conserved (3-turn (GPGR), appear to be critical for antibody binding and subsequent type-specific virus neutralization. This neutralization epitope, putatively consisting of a loop between two cysteine residues (amino acids 296 and 331) connected by a disulfide bond, is immunodominant in HIV-1-infected chimpanzees and induces antibodies restricted to the homologous viral strain.