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JAC Advance Access originally published online on April 21, 2005
Journal of Antimicrobial Chemotherapy 2005 55(6):872-878; doi:10.1093/jac/dki104
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Limited development and progression of resistance of HIV-1 to the nucleoside analogue reverse transcriptase inhibitor lamivudine in human primary macrophages

Stefano Aquaro1,*, Valentina Svicher1, Francesca Ceccherini-Silberstein1, Alessandra Cenci1, Fabbio Marcuccilli1, Sara Giannella1, Luisa Marcon2, Raffaele Caliò1, Jan Balzarini3 and Carlo-Federico Perno1

1 Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, Via Montpellier 1, 00133 Rome; 2 Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy; 3 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

* Corresponding author. Tel: +39-06-7259-6553; Fax: +39-06-7259-6039; Email: aquaro{at}uniroma2.it

Objectives: The aim of this study was to investigate the development and progression of phenotypic resistance to the HIV-1-reverse transcriptase (RT) inhibitor lamivudine, and genotypic variations of HIV-1-RT occurring under lamivudine treatment in HIV-1-infected human primary monocytes–macrophages (M/M).

Methods: Cellular passages in the presence of lamivudine were performed every 2 weeks by transferring supernatants of infected M/M to fresh M/M. A fitness assay using wild-type virus and a lamivudine-resistant HIV-1 virus (harbouring the M184V RT mutation) was performed in peripheral blood mononuclear cells. Culture supernatants were tested for p24 antigen production and RT activity. The M184V RT mutant virus was obtained by site-directed mutagenesis on a CCR5-using HIV-1 backbone.

Results: The mutagenized M184V RT virus showed full resistance to lamivudine in M/M. However, no detectable phenotypic and genotypic resistance (neither virus breakthrough, nor RT resistance-related mutations) developed in M/M infected by HIV-1 and cultured for up to seven passages in vitro (i.e. 105 days). This inefficiency of M/M to develop M184V RT mutated virus is tightly related to the low 2'-deoxynucleotide (dNTP) pool in such cells, which in turn decreases the kinetics of HIV-1-RT. Despite this, the M184V RT mutant virus replicates in M/M, although with a 30% decreased efficiency compared with the wild-type.

Conclusions: Our results show that the chances of development of resistance are far lower in M/M than in lymphocytes. This underlines the importance and the peculiar role of M/M as reservoirs of either wild-type or resistant strains in human organs.

Keywords: reservoirs , fitness , M184V


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