Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology

Abstract

Chronic immune activation is a major cause for progressive immunodeficiency in human immunodeficiency virus type-1 (HIV) infection. The underlying trigger, however, remains largely unknown. HIV single-stranded RNA is a potent immune activator by triggering Toll-like receptor (TLR) 7/8. Thus, we hypothesized that sustained TLR7 triggering induces chronic immune activation and thereby contributes to progressive immunodeficiency. We used the synthetic compound R848 or a mixture of uridine-rich HIV single-stranded (ss) RNA oligonucleotides-both are potent TLR7/8 agonists-to explore the effects of sustained TLR7 triggering on the murine lymphoid system. Sustained TLR7 triggering induced an immunopathology reminiscent of progressive lymphoid destruction in HIV disease; we observed lymphopenia, elevated proinflammatory cytokines, splenomegaly, contracted lymphoid subsets, and lymphoid microarchitecture alteration with reduced marginal zone Blymphocytes. Upon exposure to inactivated vesiculo-stomatitis virus, antibody production was abolished, although splenic lymphocytes were activated and total IgG was elevated. Our data imply that HIV itself may directly contribute to immune activation and dysfunction by stimulating TLR7. Thus, manipulation of TLR7 signaling may be a potential strategy to reduce chronic hyper-immune activation and, thereby, disease progression in HIV infection. (Blood. 2009;113:377-388) IntroductionProgressive CD4 ϩ T-cell depletion and chronic immune activation are hallmarks of HIV infection. Chronic immune activation includes aberrant cytokine production, redistribution of lymphocyte subpopulations, polyclonal B-cell activation, increased T-cell turnover, and increased numbers of activated T cells.Several observations suggest a crucial role of chronic immune activation in HIV pathogenesis: (1) Increased numbers of activated CD4 ϩ T cells expressing the activation markers CD69, CD25, and MHC class II and activated CD8 ϩ T cells expressing the activation marker CD38 correlate with HIV disease progression and CD4 ϩ T-cell loss in untreated infection; 1 (2) Immune activation is absent in nonpathogenic simian immunodeficiency virus (SIV) infection. In particular, the natural hosts of SIV, sooty mangabeys and African green monkeys, show only minimal increases in immune activation and rarely progress to immunodeficiency despite high levels of viral replication 2 ; (3) Immune activation facilitates HIV infection of T cells by promoting co-receptor, adhesion molecule, and nuclear factor (NF)-B expression; 3-5 (4) Persistent immune activation in mice that constitutively express CD70 can induce lethal T-cell immunodeficiency. 6 The precise mechanism and underlying trigger by which HIV causes immune activation remain poorly understood: Schindler and colleagues 7 noted that Nef from nonpathogenic SIV strains mediated down-modulation of the host T-cell receptor and thereby suppressed T-cell activation, whereas Nef from HIV did not. This hypothesis remains controversial when considering that only a small fraction...

Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization

“…CD4 + T cell reduction during infection has been associated not only with direct viral cytotoxicity (3), but with a more generalized state of chronic immune activation, which contributes to cell loss and to immune dysfunction, ultimately leading to disease progression (4,5). This hypothesis is corroborated by many studies indicating that: 1) during infection the markers of immune activation are increased, and they correlate with a poor prognosis (6-9); 2) proinflammatory cytokines and chemokines are expressed at high levels in the lymphoid organs of SIV-infected macaques and of HIV-1-infected patients (10-12); 3) prolonged immune activation in mice models results in T cell immunodeficiency (13) and in lymphoid architecture disruption (14); and 4) natural hosts of SIV, which despite the high viral load do not progress to AIDS, have a much lower immune activation than that found in pathogenic models of SIV infection (15).…”

“…In HIV-1-infected patients regardless of therapy and in SIV-infected macaques, migration of Th cells in response to chemotactic stimuli is impaired and is associated with perturbation of actin polymerization. Using an in vivo model (14), we demonstrate that chronic immune activation per se is sufficient to dampen Th cell migration, which can be restored by pharmacological modulation of cytoskeleton activity.…”

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

“…It was also reported that circulating pDCs in HIVinfected individuals showed an increase in IFN-a expression. 25 Baenziger et al 26 found an AIDS-like pathology in mice treated with TLR7 ligands. African green monkeys, which are considered to be the natural host of SIVagm, will not progress to AIDS even though they show high viral loads upon SIV infection.…”

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

“…S1A). Activation of the TLR7 pathway also induces a rapid increase of proinflammatory cytokines in the serum (18). To assess the impact of MyD88 deficiency on this systemic response, we analyzed serum cytokine levels 6 h after topical IMQ treatment.…”