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dc.contributor.authorYuste, Eloísa-
dc.contributor.authorBordería, Antonio V.-
dc.contributor.authorDomingo, Esteban-
dc.contributor.authorLópez-Galíndez, Cecilio-
dc.identifier.citationJournal of Virology, 2005, p. 5421-5427, Vol. 79, No. 9en_US
dc.description.abstractRepeated bottleneck passages of RNA viruses result in fitness losses due to the accumulation of deleterious mutations. In contrast, repeated transfers of large virus populations result in exponential fitness increases. Human immunodeficiency virus type 1 (HIV-1) manifested a drastic fitness loss after a limited number of plaque-to-plaque transfers in MT-4 cells. An analysis of the mutations associated with fitness loss in four debilitated clones revealed mutation frequencies in gag that were threefold higher than those in env. We now show an increase in the fitness of the debilitated HIV-1 clones by repeated passages of large populations. An analysis of the entire genomic nucleotide sequences of these populations showed that few mutations, from two to seven per clone, mediated fitness recovery. Eight of the 20 mutations affected coding regions, mainly by the introduction of nonsynonymous mutations (75%). However, most of the mutations accumulated during fitness recovery (12 of 20) were located in the 5' untranslated leader region of the genome, and more specifically, in the primer binding site (PBS) loop. Two of the viruses incorporated the same mutation in the primer activation signal in the PBS loop, which is critical for the tRNA3Lys-mediated initiation of reverse transcription. Moreover, 25% of the mutations observed were reversions. This fact, together with the presence of a large proportion of nonsynonymous replacements, may disclose the operation, during large population passages, of strong positive selection for optimal HIV-1 replication, which seems to be primarily affected by binding of the tRNA to the PBS and the initiation of reverse transcriptionen_US
dc.description.sponsorshipWork at Centro de Biología Molecular "Severo Ochoa" was supported by grant BMC 2001-1823-C02-01 and by Fundación Ramón Areces. Work in CNM was supported by grants MPY 1359/02 and MPY 1028/04 and in part by the "Red Tematica Cooperativa de Investigación en SIDA (Red de grupos 173) del FISss." A.V.B. was supported by an Instituto Carlos III fellowship. E.Y. was supported by a postdoctoral fellowship from Comunidad Autonoma de Madriden_US
dc.format.extent262470 bytes-
dc.publisherAmerican Society for Microbiologyen_US
dc.titleFew mutations in the 5' leader region mediate fitness recovery of debilitated human immunodeficiency type 1 virusesen_US
dc.description.peerreviewedPeer revieweden_US
dc.contributor.funderFundación Ramón Areces-
dc.contributor.funderMinisterio de Sanidad y Consumo (España)-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderComunidad de Madrid-
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