The function of the cellular prion protein (PrP^C) remains obscure. Studies suggest that PrP^C functions in several processes including signal transduction and Cu²⁺ metabolism. PrP^C has also been established to bind nucleic acids. Therefore we investigated the properties of PrP^C as a putative nucleic acid chaperone. Surprisingly, PrP^C possesses all the nucleic acid chaperoning properties previously specific to retroviral nucleocapsid proteins. PrP^C appears to be a molecular mimic of NCP7, the nucleocapsid protein of HIV-1. Thus PrP^C, like NCP7, chaperones the annealing of tRNA^Lys to the HIV-1 primer binding site, the initial step of retrovirus replication. PrP^C also chaperones the two DNA strand transfers required for production of a complete proviral DNA with LTRs. Concerning the functions of NCP7 during budding, PrP^C also mimics NCP7 by dimerizing the HIV-1 genomic RNA. These data are unprecedented because, although many cellular proteins have been identified as nucleic acid chaperones, none have the properties of retroviral nucleocapsid proteins. To cite this article: E. Derrington et al., C. R. Biologies 325 (2002) 17-23.