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Journal of Virology, May 2007, p. 4713-4721, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02135-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Relative Fitness and Replication Capacity of a Multinucleoside Analogue-Resistant Clinical Human Immunodeficiency Virus Type 1 Isolate with a Deletion of Codon 69 in the Reverse Transcriptase Coding Region{triangledown}

Cristina Villena,1 Julia G. Prado,1 Maria Carmen Puertas,1 Miguel Ángel Martínez,1 Bonaventura Clotet,1 Lidia Ruiz,1 Neil T. Parkin,2 Luis Menéndez-Arias,3 and Javier Martinez-Picado1,4*

irsiCaixa Foundation, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain,1 Monogram Biosciences, South San Francisco, California,2 Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas—Universidad Autónoma de Madrid, Madrid, Spain,3 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain4

Received 29 September 2006/ Accepted 14 February 2007

Deletions, insertions, and amino acid substitutions in the ß3-ß4 hairpin loop-coding region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been associated with resistance to nucleoside RT inhibitors when appearing in combination with other mutations in the RT-coding region. In this work, we have measured the in vivo fitness of HIV-1 variants containing a deletion of 3 nucleotides affecting codon 69 ({Delta}69) of the viral RT as well as the replication capacity (RC) ex vivo of a series of recombinant HIV-1 variants carrying an RT bearing the {Delta}69 deletion or the T69A mutation in a multidrug-resistant (MDR) sequence background, including the Q151M complex and substitutions M184V, K103N, Y181C, and G190A. Patient-derived viral clones having RTs with {Delta}69 together with S163I showed increased RCs under drug pressure. These data were consistent with the viral population dynamics observed in a long-term-treated HIV-1-infected patient. In the absence of drugs, viral clones containing T69A replicated more efficiently than those having {Delta}69, but only when patient-derived sequences corresponding to RT residues 248 to 527 were present. These effects could be attributed to a functional interaction between the C-terminal domain of the p66 subunit (RNase H domain) and the DNA polymerase domain of the RT. Finally, recombinant HIV-1 clones bearing RTs with MDR-associated mutations, including deletions at codon 69, showed increased susceptibilities to protease inhibitors in phenotypic assays. These effects correlated with impaired Gag cleavage and could be attributed to delayed maturation and decreased production of active protease in those variants.

* Corresponding author. Mailing address: irsiCaixa Foundation, Hospital Germans Trias i Pujol, Ctra. de Canyet s/n, 08916 Badalona, Spain. Phone: 34 93 4656374. Fax: 34 93 4653968. E-mail: jmpicado{at}irsicaixa.es

{triangledown} Published ahead of print on 21 February 2007.

Journal of Virology, May 2007, p. 4713-4721, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02135-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Puertas, M. C., Buzon, M. J., Artese, A., Alcaro, S., Menendez-Arias, L., Perno, C. F., Clotet, B., Ceccherini-Silberstein, F., Martinez-Picado, J. (2009). Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility. J. Virol. 83: 7434-7439 [Abstract] [Full Text]  


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