title: Helicobacter pylori VacA toxin inhibits human immunodeficiency virus infection of primary human T cells.
abstract: Human CD4(+) T cells are major targets for human immunodeficiency virus (HIV) infection. Resting T cells are resistant to HIV infection unless activated through the T-cell receptor (TCR) or by cytokine signals. How T-cell signaling promotes susceptibility of T cells to HIV infection remains poorly understood. Here we demonstrate that the VacA toxin produced by Helicobacter pylori can inhibit HIV infection of primary T cells, stimulated through the TCR or by cytokines alone. This activity of VacA was dependent on its ability to form membrane channels. VacA suppressed HIV infection of T cells at a stage after viral entry, post-reverse transcription and pre-two-long-terminal-repeat circle formation, similar to the cytokine signaling inhibitor rapamycin. Mechanistically, neither VacA nor rapamycin inhibited the activation of cytokine signal transduction components (STAT5, p42/44 mitogen-activated protein kinase, or p38), but both blocked activation of key regulatory proteins required for G(1) cell cycle transition. In contrast to rapamycin, VacA did not suppress phosphorylation of p70 S6 kinase but caused mitochondrial depolarization and ATP depletion within primary T cells. These results suggest that VacA inhibits T-cell activation and HIV infection via a novel mechanism. Identifying the host cell targets of VacA could be useful for elucidating the HIV life cycle within primary T cells.
authors.affiliation: Division of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kyra
authors.initials: K
authors.lastname: Oswald-Richter
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
authors.forename: Scott E
authors.initials: SE
authors.lastname: VanCompernolle
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Cover
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
mesh_terms: D001426:Bacterial Proteins / Q000494:pharmacology*; D002460:Cell Line; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; C074689:VacA protein, Helicobacter pylori