title: Endothelial cells promote human immunodeficiency virus replication in nondividing memory T cells via Nef-, Vpr-, and T-cell receptor-dependent activation of NFAT.
abstract: Human endothelial cells (ECs) enhance human immunodeficiency virus (HIV) replication within CD4(+) memory T cells by 50,000-fold in a Nef-dependent manner. Here, we report that EC-mediated HIV type 1 replication is also dependent on an intact vpr gene. Moreover, we demonstrate that despite a requirement for engaging major histocompatibility complex (MHC) class II molecules and costimulators, EC-stimulated virus-producing cells (p24(high) T cells) do not proliferate, nor are they arrested in the cell cycle. Rather, they are minimally activated, sometimes expressing CD69 but not CD25, HLA-DR, VLA-1, or effector cytokines. Blocking antibodies to interleukin 2 (IL-2), IL-6, IL-7, or tumor necrosis factor do not inhibit viral replication. Cyclosporine effectively inhibits viral replication, as does disruption of the NFAT binding site in the viral long terminal repeat. Furthermore, in the presence of ECs, suboptimal T-cell receptor (TCR) stimulation with phytohemagglutinin L supports efficient viral replication, and suboptimal stimulation with toxic shock syndrome toxin 1 leads to viral replication selectively in the TCR-stimulated, Vbeta2-expressing T cells. Collectively, these data indicate that ECs provide signals that promote Nef- and Vpr-dependent HIV replication in memory T cells that have been minimally activated through their TCRs. Our studies suggest a mechanism for HIV replication in vivo within the reservoir of circulating memory CD4(+) T cells that persist despite antiretroviral therapy and further suggest that maintenance of immunological memory by MHC class II-expressing ECs via TCR signaling may contribute to HIV rebound following cessation of antiretroviral therapy.
authors.affiliation: Section of Immunology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Choi
authors.forename: Jason
authors.initials: J
authors.lastname: Walker
authors.forename: Kristina
authors.initials: K
authors.lastname: Talbert-Slagle
authors.forename: Paulette
authors.initials: P
authors.lastname: Wright
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: Louis
authors.initials: L
authors.lastname: Alexander
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism; D016334:Genes, vpr / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016282:Aspartic Acid Endopeptidases; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D000099192:CD69 Antigens; C475087:NFAM1 protein, human; C498549:NAPSA protein, human