Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses.
Dendritic cells (DCs) in mucosal surfaces are early targets for human immunodeficiency virus-1 (HIV-1). DCs mount rapid and robust immune responses upon pathogen encounter. However, immune response in the early events of HIV-1 transmission appears limited, suggesting that HIV-1 evade early immune control by DCs. We report that HIV-1 induces a rapid shutdown of autophagy and immunoamphisomes in DCs. HIV-1 envelope activated the mammalian target of rapamycin pathway in DCs, leading to autophagy exhaustion. HIV-1-induced inhibition of autophagy in DC increased cell-associated HIV-1 and transfer of HIV-1 infection to CD4(+) T cells. HIV-1-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs represent a pathogenesis mechanism that can be pharmacologically countered with therapeutic and prophylactic implications.
Blanchet
Fabien P
FP
Department of Dermatology, University Hospital and Medical School of Geneva, 1211 Geneva, Switzerland.
Moris
Arnaud
A
Nikolic
Damjan S
DS
Lehmann
Martin
M
Cardinaud
Sylvain
S
Stalder
Romaine
R
Garcia
Eduardo
E
Dinkins
Christina
C
Leuba
Florence
F
Wu
Li
L
Schwartz
Olivier
O
Deretic
Vojo
V
Piguet
Vincent
V
D056704:Adaptive Immunity; D001343:Autophagy; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015536:Down-Regulation; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000276:immunology / Q000821:virology; D008969:Molecular Sequence Data; D010588:Phagosomes / Q000276:immunology* / Q000821:virology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
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