title: Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.
abstract: The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.
authors: UPR 9002 du CNRS conventionnée à l'Université Louis Pasteur, IBMC 15 rue René Descartes, 67084, Strasbourg cedex, France.
authors: Eric
authors: E
authors: Ennifar
authors: Jean-Christophe
authors: JC
authors: Paillart
authors: Anne
authors: A
authors: Bodlenner
authors: Philippe
authors: P
authors: Walter
authors: Jean-Marc
authors: JM
authors: Weibel
authors: Anne-Marie
authors: AM
authors: Aubertin
authors: Patrick
authors: P
authors: Pale
authors: Philippe
authors: P
authors: Dumas
authors: Roland
authors: R
authors: Marquet