RT info:eu-repo/semantics/article
T1 High Sequence Conservation of Human Immunodeficiency Virus Type 1 Reverse Transcriptase under Drug Pressure despite the Continuous Appearance of Mutations
A1 Ceccherini Silberstein, Francesca
A1 Gago Badenas, Federico
A1 Santoro, Maria Mercedes
A1 Gori, Caterina
A1 Svicher, Valentina
A1 Rodríguez Barrios, Fátima
A1 d'Arrigo, Roberta
A1 Ciccozzi, Massimo
A1 Bertoli, Ada
A1 d'Arminio Monforte, Antonella
A1 Balzarini, Jan
A1 Antinori, Andrea
A1 Perno, Carlo Federico
K1 Ciencia
K1 Farmacología
K1 Science
K1 Pharmacology
AB To define the extent of sequence conservation in human immunodeficiency virus type 1 (HIV-1) reversetranscriptase (RT) in vivo, the first 320 amino acids of RT obtained from 2,236 plasma-derived samples froma well-defined cohort of 1,704 HIV-1-infected individuals (457 drug na¿¿ve and 1,247 drug treated) were analyzedand examined in structural terms. In na¿¿ve 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 29consecutive residues. Of the nine longest invariant regions identified, some contained residues and domainscritical for enzyme stability and function. In patients treated with RT inhibitors, despite profound drugpressure 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 suggeststhat participation of consecutive residues in structural domains is strictly required for cooperative functionsand sustainability of HIV-1 RT activity. Besides confirming the conservation of amino acids that are alreadyknown to be important for catalytic activity, stability of the heterodimer interface, and/or primer/templatebinding, the other 62 new invariable residues are now identified and mapped onto the three-dimensionalstructure of the enzyme. This new knowledge could be of help in the structure-based design of novel resistanceevadingdrugs.
PB American Society for Microbiology
YR 2005
FD 2005
LK http://hdl.handle.net/10017/5122
UL http://hdl.handle.net/10017/5122
LA eng
DS MINDS@UW
RD 25-abr-2024