MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands.
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.
Meier
Angela
A
Partners AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Boston, MA 02129, USA.
Alter
Galit
G
Frahm
Nicole
N
Sidhu
Harlyn
H
Li
Bin
B
Bagchi
Aranya
A
Teigen
Nickolas
N
Streeck
Hendrik
H
Stellbrink
Hans-Juergen
HJ
Hellman
Judith
J
van Lunzen
Jan
J
Altfeld
Marcus
M
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
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