title: HIV-1 infection of macrophages dysregulates innate immune responses to Mycobacterium tuberculosis by inhibition of interleukin-10.
abstract: Human immunodeficiency virus (HIV)-1 and Mycobacterium tuberculosis (M. tuberculosis) both target macrophages, which are key cells in inflammatory responses and their resolution. Therefore, we tested the hypothesis that HIV-1 may modulate macrophage responses to coinfection with M. tuberculosis. HIV-1 caused exaggerated proinflammatory responses to M. tuberculosis that supported enhanced virus replication, and were associated with deficient stimulus-specific induction of anti-inflammatory interleukin (IL)-10 and attenuation of mitogen-activated kinase signaling downstream of Toll-like receptor 2 and dectin-1 stimulation. Our in vitro data were mirrored by lower IL-10 and higher proinflammatory IL-1β in airway samples from HIV-1-infected patients with pulmonary tuberculosis compared with those with non-tuberculous respiratory tract infections. Single-round infection of macrophages with HIV-1 was sufficient to attenuate IL-10 responses, and antiretroviral treatment of replicative virus did not affect this phenotype. We propose that deficient homeostatic IL-10 responses may contribute to the immunopathogenesis of active tuberculosis and propagation of virus infection in HIV-1/M. tuberculosis coinfection.
authors.affiliation: Infection and Immunity, University College London.
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Tomlinson
authors.forename: Lucy C K
authors.initials: LC
authors.lastname: Bell
authors.forename: Naomi F
authors.initials: NF
authors.lastname: Walker
authors.forename: Jhen
authors.initials: J
authors.lastname: Tsang
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Brown
authors.forename: Ronan
authors.initials: R
authors.lastname: Breen
authors.forename: Marc
authors.initials: M
authors.lastname: Lipman
authors.forename: David R
authors.initials: DR
authors.lastname: Katz
authors.forename: Robert F
authors.initials: RF
authors.lastname: Miller
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Chain
authors.forename: Paul T G
authors.initials: PT
authors.lastname: Elkington
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
mesh_terms: D002478:Cells, Cultured; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000276:immunology*
chemical_list: D016753:Interleukin-10
keywords: HIV-1; inflammation; interleukin-10; macrophage; tuberculosis