title: Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation.
abstract: Plasmacytoid dendritic cells (pDC) contribute to antiviral immunity mainly through recognition of microbial products and viruses via intracellular Toll-like receptor 7 (TLR7) or TLR9, resulting in the production of type I interferons (IFNs). Although interferons reduce the viral burden in the acute phase of infection, their role in the chronic phase is unclear. The presence of elevated plasma IFN-alpha levels in advanced HIV disease and its association with microbial translocation in chronic HIV infection lead us to hypothesize that IFN-alpha could contribute to immune activation. Blocking of IFN-alpha production using chloroquine, an endosomal inhibitor, was tested in a novel in vitro model system with the aim of characterizing the effects of chloroquine on HIV-1-mediated TLR signaling, IFN-alpha production, and T-cell activation. Our results indicate that chloroquine blocks TLR-mediated activation of pDC and MyD88 signaling, as shown by decreases in the levels of the downstream signaling molecules IRAK-4 and IRF-7 and by inhibition of IFN-alpha synthesis. Chloroquine decreased CD8 T-cell activation induced by aldrithiol-2-treated HIV-1 in peripheral blood mononuclear cell cultures. In addition to blocking pDC activation, chloroquine also blocked negative modulators of the T-cell response, such as indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PDL-1). Our results indicate that TLR stimulation and production of IFN-alpha by pDC contribute to immune activation and that blocking of these pathways using chloroquine may interfere with events contributing to HIV pathogenesis. Our results suggests that a safe, well-tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with highly active antiretroviral therapy to control immune activation in HIV-1 infection.
authors: Department of Immunology and Microbiology, Rush University Medical Center, 1735 West Harrison St. (Cohn Research Building, Lab 641), Chicago, IL 60612, USA.
authors: Jeffrey A
authors: JA
authors: Martinson
authors: Carlos J
authors: CJ
authors: Montoya
authors: Xiomara
authors: X
authors: Usuga
authors: Rollie
authors: R
authors: Ronquillo
authors: Alan L
authors: AL
authors: Landay
authors: Seema N
authors: SN
authors: Desai
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000187:drug effects*; D051199:Toll-Like Receptor 7 / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D002738:Chloroquine