title: High sequence conservation of human immunodeficiency virus type 1 reverse transcriptase under drug pressure despite the continuous appearance of mutations.
abstract: To define the extent of sequence conservation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in vivo, the first 320 amino acids of RT obtained from 2,236 plasma-derived samples from a well-defined cohort of 1,704 HIV-1-infected individuals (457 drug naïve and 1,247 drug treated) were analyzed and examined in structural terms. In naïve patients, 233 out of these 320 residues (73%) were conserved (<1% variability). The majority of invariant amino acids clustered into defined regions comprising between 5 and 29 consecutive residues. Of the nine longest invariant regions identified, some contained residues and domains critical for enzyme stability and function. In patients treated with RT inhibitors, despite profound drug pressure and the appearance of mutations primarily associated with resistance, 202 amino acids (63%) remained highly conserved and appeared mostly distributed in regions of variable length. This finding suggests that participation of consecutive residues in structural domains is strictly required for cooperative functions and sustainability of HIV-1 RT activity. Besides confirming the conservation of amino acids that are already known to be important for catalytic activity, stability of the heterodimer interface, and/or primer/template binding, the other 62 new invariable residues are now identified and mapped onto the three-dimensional structure of the enzyme. This new knowledge could be of help in the structure-based design of novel resistance-evading drugs.
authors.affiliation: Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. ceccherini@med.uniroma2.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Maria
authors.initials: M
authors.lastname: Santoro
authors.forename: Caterina
authors.initials: C
authors.lastname: Gori
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Fátima
authors.initials: F
authors.lastname: Rodríguez-Barrios
authors.forename: Roberta
authors.initials: R
authors.lastname: d'Arrigo
authors.forename: Massimo
authors.initials: M
authors.lastname: Ciccozzi
authors.forename: Ada
authors.initials: A
authors.lastname: Bertoli
authors.forename: Antonella
authors.initials: A
authors.lastname: d'Arminio Monforte
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Carlo-Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D017124:Conserved Sequence; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase