Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses

Immunity. 2010 May 28;32(5):654-69. doi: 10.1016/j.immuni.2010.04.011. Epub 2010 May 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Autophagy
  • Base Sequence
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Dendritic Cells / virology*
  • Down-Regulation
  • Flow Cytometry
  • HIV Infections / immunology*
  • HIV-1 / physiology*
  • Humans
  • Immunity, Innate*
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / immunology
  • Lysosomes / virology
  • Molecular Sequence Data
  • Phagosomes / immunology*
  • Phagosomes / virology
  • Protein-Serine-Threonine Kinases / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases

Substances

  • Intracellular Signaling Peptides and Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1