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R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L^– CD4⁺ T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

Françoise Gondois-Rey,^1,2 Angelique Biancotto,^1,3 Marcelo Antonio Fernandez,¹ Lise Bettendroffer,¹ Jana Blazkova,^1,4, Katerina Trejbalova,^1,4, Marjorie Pion,^1, and Ivan Hirsch^1,4*

Institut National de la Santé et de la Recherche Médicale (INSERM) U372,¹ IFR 137,² UMR 599, 27, boulevard Lei Roure, 13009 Marseille, France,⁴ Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland 20892³

Received 19 May 2005/ Accepted 27 October 2005

The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4⁺ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4⁺ T cells on the predominance of R5 and X4 HIV-1 variants in different subsets of CD4⁺ T cells in ex vivo-infected human lymphoid tissues and peripheral blood mononuclear cells (PBMCs). In these cell systems, we examined the sensitivity of HIV replication to reverse transcriptase inhibitors. We demonstrate that R5 HIV-1 variants preferentially produced productive infection in HLA-DR^– CD62L^– CD4⁺ T cells. These cells were mostly in the G₁b phase of the cell cycle, divided slowly, and expressed high levels of CCR5. In contrast, X4 HIV-1 variants preferentially produced productive infection in activated HLA-DR⁺ CD62L⁺ CD4⁺ T cells, which expressed high levels of CXCR4. The abilities of the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine to stop HIV-1 replication were 20 times greater in activated T cells than in slowly dividing HLA-DR^– CD62L^– CD4⁺ T cells. This result, demonstrated both in a highly physiologically relevant ex vivo lymphoid tissue model and in PBMCs, correlated with higher levels of thymidine kinase mRNA in activated than in slowly dividing HLA-DR^– CD62L^– CD4⁺ T cells. The non-NRTI nevirapine was equally efficient in both cell subsets. The lymphoid tissue and PBMC-derived cell systems represent well-defined models which could be used as new tools for the study of the mechanism of resistance to HIV-1 inhibitors in HLA-DR^– CD62L^– CD4⁺ T cells.

Present address: Institute of Molecular Genetics, 16637 Prague, Czech Republic.

Present address: Department of Dermatology and Venerology, University Hospital of Geneva, 1211 Geneva, Switzerland.

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