Abstract
Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology.
Highlights
Chronic immune activation is a driving factor in CD4+ T cell loss and disease progression in human immunodeficiency virus (HIV)-infected individuals, yet the mechanisms responsible for this process are not completely understood [1]
Produced abundant IFN-a and TNF-a in response to inactivated SIVmac239 particles (iSIV) and influenza virus, which was potently blocked by DV056 (Figure 1B). Plasmacytoid dendritic cells (pDC) were the exclusive producers of IFN-a in simian immunodeficiency virus (SIV)-naive blood in response to stimulation with iSIV, live SIV, influenza virus and the TLR9 agonist CpG-C, as shown by the lack of IFN-a secretion from stimulated Peripheral blood mononuclear cells (PBMC) that were depleted of pDC (Figure 1C)
We have demonstrated that stimulation of pDC by viral RNA through engagement of TLR7 and TLR9 induces a robust but transient IFN-a response in the lymph nodes of SIVinfected rhesus macaques, and provide evidence that this response in itself is insufficient to drive persistent IFN-stimulated genes (ISG) expression and immune activation that distinguishes pathogenic from nonpathogenic models [13,14,15]
Summary
Chronic immune activation is a driving factor in CD4+ T cell loss and disease progression in HIV-infected individuals, yet the mechanisms responsible for this process are not completely understood [1]. A key distinction between the two models is that the innate immune response is rapidly resolved in SIV-infected natural hosts, whereas upregulation of the type I interferon (IFN) response and expression of IFN-stimulated genes (ISG) persists in SIV-infected macaques [12,13,14,15,16,17]. This dichotomy suggests that the innate immune response and persistent type I IFN production in particular may play a key role in chronic immune activation and disease progression [18,19]
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