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J. Virol. doi:10.1128/JVI.02135-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Relative fitness and replication capacity of a multi-nucleoside analogue-resistant clinical HIV-1 isolate with a deletion of codon 69 in the reverse transcriptase

irsiCaixa Foundation, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain; Monogram Biosciences, South San Francisco, CA, USA; Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid), Madrid, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

^* To whom correspondence should be addressed. Email: jmpicado{at}irsicaixa.es.

	Abstract

Deletions, insertions and amino acid substitutions in the 3-4 hairpin-loop-coding region of HIV-1 reverse transcriptase (RT) have been associated with resistance to nucleoside RT inhibitors, when appearing in combination with other mutations in RT-coding region. In this work, we have measured the in vivo fitness of HIV-1 variants containing a deletion of three nucleotides affecting codon 69 (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 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 69 together with S163I showed increased RC 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 69, but only when patient-derived sequences corresponding to RT residues 248-527 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 multiple drug-resistance associated mutations, including deletions at codon 69, showed increased susceptibility 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.