XVIII International AIDS Conference

Abstract

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Unique functional properties of dendritic cells in HIV-1 elite controllers

Presented by Mathias Lichterfeld (United States).

J. Huang1, P. Burke1, F. Peyrera1, B. Walker1, L. Borges2, M. Lichterfeld3, X.G. Yu1


1Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Charlestown, United States, 2Amgen Inc., Seattle, United States, 3Infectious Disease Division, Massachusetts General Hospital, Boston, United States

Background: “Elite” controllers are HIV-1 infected patients who maintain undetectable levels of HIV-1 viremia in the absence of antiretroviral therapy. The Identification of unique immunological characteristics in this specific patient population is a premier opportunity for determining components of immune protection against HIV-1.
Methods: Antigen-presenting properties of freshly isolated myeloid dendritic cells (mDC) were analyzed in mixed lymphocyte reactions (MLR), followed by immunophenotypic characterization of responding allogeneic T cells. Surface expression of leukocyte Immunoglobulin like receptors (ILT) was analyzed by multiparameter flow cytometry. Secretion of pro-inflammatory cytokines was detected using intracellular cytokine staining. Targeted siRNA mediated gene knockout and specific blocking antibodies were used to determine the specific functional effects mediated by ILT receptors.
Results: In comparison to HIV-1 progressors or HIV-1 negative persons, mDC from “elite” controllers had significantly (p< 0.001) better antigen-presenting properties, as determined by MLRs. Moreover, elite controllers preferentially induced memory-cell like allostimulatory responses with upregulation of CD62L, CD127 and downregulation of CD57. In contrast, mDC from elite controllers had weaker abilities to secrete pro-inflammatory cytokines (TNF-a, IL-6 and IL-12p70) in comparison to HIV-1 progressors or HIV-1 negative persons. This unique functional profile was associated with a selective, highly significant (p< 0.01) phenotypic upregulation of the immunoregulatory receptors ILT2 and ILT5 on mDC in elite controllers. Inhibition of ILT2 or ILT5 with siRNA or blocking antibodies led to significant reduction of the antigen-presenting properties of dendritic cells, consistent with an immunostimulatory effect of these receptors on dendritic cell function.
Conclusions: HIV-1 “elite” controllers have myeloid dendritic cells with a unique combination of increased antigen-presenting and decreased cytokine-section properties. This extraordinary functional profile is mediated and maintained by upregulation of the immunomodulatory receptors ILT2 and ILT5. Manipulation of ILT-mediated dendritic cell function might thus represent a promising strategy for immunological approaches to treatment and prevention of HIV-1 infection.


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