title: Effect of tenofovir on nucleotidases and cytokines in HIV-1 target cells.
abstract: Tenofovir (TFV) has been widely used for pre-exposure prophylaxis of HIV-1 infection with mixed results. While the use of TFV in uninfected individuals for prevention of HIV-1 acquisition is actively being investigated, the possible consequences of TFV exposure for the HIV-target cells and the mucosal microenvironment are unknown. In the current study, we evaluated the effects of TFV treatment on blood-derived CD4⁺ T cells, monocyte-derived macrophages and dendritic cells (DC). Purified HIV-target cells were treated with different concentrations of TFV (0.001-1.0 mg/ml) for 2 to 24 hr. RNA was isolated and RT-PCR was performed to compare the levels of mRNA expression of nucleotidases and pro-inflammatory cytokine genes (MIP3α, IL-8 and TNFα) in the presence or absence of TFV. We found that TFV increases 5'-ecto-nucleotidase (NT5E) and inhibits mitochondrial nucleotidase (NT5M) gene expression and increases 5' nucleotidase activity in macrophages. We also observed that TFV stimulates the expression and secretion of IL-8 by macrophages, DC, and activated CD4⁺ T cells and increases the expression and secretion of MIP3α by macrophages. In contrast, TFV had no effect on TNFα secretion from macrophages, DC and CD4⁺ T cells. Our results demonstrate that TFV alters innate immune responses in HIV-target cells with potential implications for increased inflammation at mucosal surfaces. As new preventive trials are designed, these findings should provide a foundation for understanding the effects of TFV on HIV-target cells in microbicide trials.
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Biswas
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez-Garcia
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Crist
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shen
authors.forename: Jack E
authors.initials: JE
authors.lastname: Bodwell
authors.forename: John V
authors.initials: JV
authors.lastname: Fahey
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D000068698:Tenofovir; D013997:Time Factors
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D063065:Organophosphonates; D000068698:Tenofovir; D015720:5'-Nucleotidase; D000225:Adenine