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Journal of Virology, May 2005, p. 5421-5427, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5421-5427.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Few Mutations in the 5' Leader Region Mediate Fitness Recovery of Debilitated Human Immunodeficiency Type 1 Viruses

Eloísa Yuste ,1,2,{dagger},{ddagger} Antonio V. Bordería,2,{dagger} Esteban Domingo,1 and Cecilio López-Galíndez2*

Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma, Cantoblanco,1 Servicio de Virologia Molecular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain2

Received 8 October 2004/ Accepted 15 December 2004

Repeated 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 transcription.

* Corresponding author. Mailing address: Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera de Pozuelo Km 2, Majadahonda, 28220 Madrid, Spain. Phone: 34 91 822 39 18. Fax: 34 91 509 79 19. E-mail: clopez{at}isciii.es.

{dagger} E.Y. and A.V.B. contributed equally to this work.

{ddagger} Present address: New England Primate Research Center, Harvard Medical School, Southborough, MA 01772-9102.

Journal of Virology, May 2005, p. 5421-5427, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5421-5427.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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