Abstract
Circulating plasmacytoid dendritic cells (pDC) decline during HIV-1 infection, but at the same time they express markedly higher levels of interferon alpha (IFNα), which is associated with HIV-1 disease progression. Here we show an accumulation of pDC in lymph nodes (LN) of treatment-naïve HIV-1 patients. This phenomenon was associated with elevated expression of the LN homing marker, CCR7, on pDC in peripheral blood of HIV-1 patients, which conferred increased migratory capacity in response to CCR7 ligands in ex vivo functional assays. LN-homed pDC of HIV-1 patients presented higher CD40 and lower BDCA2 levels, but unchanged CD83 and CD86 expression. In addition, these cells expressed markedly higher amounts of IFNα compared to uninfected individuals, and were undergoing faster rates of cell death. These results demonstrate for the first time that in asymptomatic, untreated HIV-1 patients circulating pDC up-regulate CCR7 expression, accumulate in lymph nodes, and express high amounts of IFNα before undergoing cell death. Since IFNα inhibits cell proliferation and modulates immune responses, chronically high levels of this cytokine in LN of HIV-1 patients may impair differentiation and immune function of bystander CD4+ T cells, thus playing into the mechanisms of AIDS immunopathogenesis.
Highlights
Untreated HIV-1 infection is characterized by a progressive decline of CD4+ T cell number and function
In the present report we investigated fate, activation, maturation, and function of plasmacytoid dendritic cells during HIV-1 disease
Virus infection [15,50], several groups reported the gradual decline of plasmacytoid dendritic cells (pDC) in peripheral blood of HIV-1 patients [16,18,19]
Summary
Untreated HIV-1 infection is characterized by a progressive decline of CD4+ T cell number and function. Recent studies have shown that CD4+ T cells are rapidly depleted from the gutassociated lymphoid tissue (GALT) and other mucosal sites within the first few weeks of infection (for a comprehensive review see [1]). Mucosal depletion of CD4+ T cells is followed by the onset of generalized immune activation and progressive loss of immune function, which are manifested throughout the asymptomatic chronic phase of the disease [1]. Interferon alpha (IFNa) is rapidly upregulated in response to viral infections [7,8,9], and is an essential player in antiviral immune responses: it induces the expression of cellular genes that interfere with viral replication, activates NK cell function, and promotes maturation of antigen presenting cells [10,11,12,13,14]. Plasmacytoid dendritic cells (pDC) are the main IFNa producers in humans [15]
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