title: R5 variants of human immunodeficiency virus type 1 preferentially infect CD62L- CD4+ T cells and are potentially resistant to nucleoside reverse transcriptase inhibitors.
abstract: 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.
authors.affiliation: INSERM U372, boulevard Lei Roure, 13009 Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Gondois-Rey
authors.forename: Angelique
authors.initials: A
authors.lastname: Biancotto
authors.forename: Marcelo Antonio
authors.initials: MA
authors.lastname: Fernandez
authors.forename: Lise
authors.initials: L
authors.lastname: Bettendroffer
authors.forename: Jana
authors.initials: J
authors.lastname: Blazkova
authors.forename: Katerina
authors.initials: K
authors.lastname: Trejbalova
authors.forename: Marjorie
authors.initials: M
authors.lastname: Pion
authors.forename: Ivan
authors.initials: I
authors.lastname: Hirsch
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002478:Cells, Cultured; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D006684:HLA-DR Antigens; D006801:Humans; D019041:L-Selectin / Q000235:genetics; D007963:Leukocytes, Mononuclear; D008213:Lymphocyte Activation; D014066:Palatine Tonsil; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013045:Species Specificity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D006684:HLA-DR Antigens; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D018894:Reverse Transcriptase Inhibitors; D019041:L-Selectin