Research Article: Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Date Published: July 25, 2013

Publisher: Public Library of Science

Author(s): Muhamuda Kader, Amanda P. Smith, Cristiana Guiducci, Elizabeth R. Wonderlich, Daniel Normolle, Simon C. Watkins, Franck J. Barrat, Simon M. Barratt-Boyes, Guido Silvestri.


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.

Partial Text

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]. Recent comparative studies in nonhuman primate models have shed light on the etiology of chronic immune activation [2]. Pathogenic simian immunodeficiency virus (SIV) infection in non-natural hosts including the Asian macaque species is characterized by sustained depletion of peripheral and mucosal CD4+ T cells, microbial translocation across the gut mucosa and persistently high levels of proinflammatory cytokines and lymphocyte activation that culminate in disease progression and AIDS [3]–[7]. In contrast, SIV infection of natural hosts such as the African green monkey and sooty mangabey results in preserved T cell homeostasis, low levels of chronic immune activation and a benign clinical course despite high levels of circulating virus [8]–[11]. 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]–[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].

This study is the first to directly dissect the role of innate immunity in driving immune activation in pathogenic SIV infection of rhesus macaques, a model that produces AIDS-like disease very similar to HIV infection in humans but with an accelerated time frame [47]. We have demonstrated that stimulation of pDC by viral RNA through engagement of TLR7 and TLR9 induces a robust but transient IFN-α response in the lymph nodes of SIV-infected rhesus macaques, and provide evidence that this response in itself is insufficient to drive persistent ISG expression and immune activation that distinguishes pathogenic from nonpathogenic models [13]–[15].




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