Blood Journal
Leading the way in experimental and clinical research in hematology

Over-activation of plasmacytoid dendritic cell inhibits anti-viral T-cell responses: a model for HIV immunopathogenesis

  1. Adriano Boasso1,*,
  2. Caroline M Royle1,
  3. Spyridon Doumazos1,
  4. Veronica N Aquino2,
  5. Mara Biasin3,
  6. Luca Piacentini3,
  7. Barbara Tavano3,
  8. Dietmar Fuchs4,
  9. Francesco Mazzotta5,
  10. Sergio Lo Caputo5,
  11. Gene M Shearer6,
  12. Mario Clerici7, and
  13. David R Graham2
  1. 1 Immunology Section, Chelsea and Westminster Hospital, Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Imperial College, London, United Kingdom;
  2. 2 Retrovirus Laboratory, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States;
  3. 3 Cattedra di Immunologia, Universita degli Studi di Milano, Milan, Italy;
  4. 4 Division of Biological Chemistry Biocentre, Innsbruck Medical University, Innsbruck, Austria;
  5. 5 Divisione Malattie Infettive, Ospedale S.M. Annunziata, Florence, Italy;
  6. 6 Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States;
  7. 7 Fondazione Don Gnocchi IRCCS, Milan, Italy
  1. * Corresponding author; email: a.boasso{at}imperial.ac.uk

Abstract

A delicate balance between immunostimulatory and immunosuppressive signals mediated by dendritic cells (DC) and other antigen-presenting cells (APC) regulates the strength and efficacy of anti-viral T cell responses. The human immunodeficiency virus (HIV) is a potent activator of plasmacytoid DC (pDC). Chronic pDC activation by HIV promotes the pathogenesis of the acquired human immunodeficiency syndrome (AIDS). Cholesterol is pivotal in maintaining HIV envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, we generated virions with reduced ability to activate pDC. We found that APC activation was dissociated from the induction of type I interferon (IFN-α/β) and indoleamine 2,3-dioxygenase-mediated immunosuppression in vitro. Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T cell responses in HIV-exposed uninfected individuals. These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/β.

  • Submitted March 23, 2011.
  • Accepted September 8, 2011.