3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

DISRUPTED INTERACTIONS BETWEEN DENDRITIC CELLS AND NATURAL KILLER CELLS IN HIV-1 INFECTED VIREMIC INDIVIDUALS

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. MoOa0306

Mavilio D.¹, Lombardo G.¹, Kim D.¹, Ortolano S.¹, La Sala A.², Daucher M.¹, O'Shea A.¹, Kovacs C.³, Marcenaro E.⁴, Moretta A.⁴, Fauci A.S.^1
1National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, United States of America, ²Istituto San Raffaele, IRCCS, Rome, 00163, Italy, ³Department of Medicine, University of Toronto, Toronto, Ontario, M5S1A1, Canada, ⁴Dipartimento di Medicina Sperimentale, University of Genova, Genova, 16132, Italy

BACKGROUND: Reciprocal Interactions of Natural Killer (NK) cells and Dendritic Cells (DCs) influence the adaptive immune response as well as innate NK cell functions. This cross-talking requires both cell to cell contact through different NK receptors and the secretion of several cytokines that lead to the DC maturation or to the killing of immature (i)DCs by NK cells. The aim of this study was to characterize the disruption of the NK-DC interactions in HIV-1 infection.

METHODS: NK cells and DCs were isolated from PBMCs of 15 healthy HIV-1 uninfected subjects, 15 viremic and 15 aviremic HIV-infected subjects receiving antiretroviral therapy. iDCs were generated from monocytes stimulated with rIL-4 and GM-CSF for 6 days; mature (m)DCs were generated by overnight stimulation with LPS and IFN-γ. Autologous NK cells were obtained by negative selection of PBMCs. We tested the ability of NK cells to kill iDC by a Cr51 release assay and fluorescence microscopy; the activation of NK cells driven by mDCs in a Mixed Lymphocyte Reaction; and cytokine secretion by ELISA.

RESULTS: NK cells isolated from HIV+ viremic, but not HIV+ aviremic, individuals were dramatically impaired in their ability to kill autologous iDCs in vitro, as compared those of uninfected donors. This defect was highly associated with significantly reduced NK cell expression of NKp30 and decreased NK expression and secretion of TNF-α related apoptosis inducing ligand (TRAIL) and s-TRAIL, respectively. Moreover, mDCs from viremic HIV-1 infected subjects produced lower levels of IL-10 and IL-12. Under these circumstances, mDCs from HIV-1 patients were not able to activate and induce proliferation of NK cells, which in turn, failed to kill iDCs.

CONCLUSIONS: The disrupted NK-DC interactions occurring in HIV-1 infected viremic individuals is a possible explanation for the impaired adaptive immune response to HIV and may lead to a defective clearance of HIV-infected cells.

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Basic | MoOa0306 | Domenico Mavilio

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