title: MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands.
abstract: Immune activation is a major characteristic of human immunodeficiency virus type 1 (HIV-1) infection and a strong prognostic factor for HIV-1 disease progression. The underlying mechanisms leading to immune activation in viremic HIV-1 infection, however, are not fully understood. Here we show that, following the initiation of highly active antiretroviral therapy, the immediate decline of immune activation is closely associated with the reduction of HIV-1 viremia, which suggests a direct contribution of HIV-1 itself to immune activation. To propose a mechanism, we demonstrate that the single-stranded RNA of HIV-1 encodes multiple uridine-rich Toll-like receptor 7/8 (TLR7/8) ligands that induce strong MyD88-dependent plasmacytoid dendritic cell and monocyte activation, as well as accessory cell-dependent T-cell activation. HIV-1-encoded TLR ligands may, therefore, directly contribute to the immune activation observed during viremic HIV-1 infection. These data provide an initial rationale for inhibiting the TLR pathway to directly reduce the chronic immune activation induced by HIV-1 and the associated immune pathogenesis.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Boston, MA 02129, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Meier
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Harlyn
authors.initials: H
authors.lastname: Sidhu
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Aranya
authors.initials: A
authors.lastname: Bagchi
authors.forename: Nickolas
authors.initials: N
authors.lastname: Teigen
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Stellbrink
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
authors.forename: Jan
authors.initials: J
authors.lastname: van Lunzen
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D015658:HIV Infections / Q000276:immunology / Q000628:therapy; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007107:Immune System / Q000502:physiology*; D015850:Interleukin-6 / Q000276:immunology; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014529:Uridine / Q000378:metabolism; D014766:Viremia
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D015850:Interleukin-6; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D009841:Oligonucleotides; D012367:RNA, Viral; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D014529:Uridine