Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

et al. (2014) Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice. PLoS Pathog 10(7): e1004291. doi:10.1371/journal.ppat.1004291 Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice Guangming Li 0 Menglan Cheng 0 Jun-ichi Nunoya 0 Liang Cheng 0 Haitao Guo 0 Haisheng Yu 0 Yong- jun Liu 0 Lishan Su 0 Liguo Zhang 0 Guido Silvestri, Emory University, United States of America 0 1 Key Lab of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences , Beijing , China , 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 3 Baylor Institute for Immunology Research, Baylor Research Institute , Dallas, Texas , United States of America, 4 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina , United States of America The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDCdepleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDCdepleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was supported in part by grants from Ministry of Health, China (2013ZX10001-002 and 2012ZX10001-003 to LZ). This work was also supported by UNC University Cancer Research Fund innovation grant, from the US National Institutes of Health (AI080432, AI077454 and AI095097 to LS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: I have read the journals policy and the authors of this manuscript have the following competing interests: pending patent application for the pDC depleting monoclonal antibody. This does not alter our adherence to all PLOS policies on sharing data and materials. Chronic immune activation induced by HIV-1 infection is highly correlated with CD4 T cell depletion and immunodeficiency [1,2,3]. The level of T cell activation (HLADR+CD38+CD8+ T cells) is correlated with disease progression independent of HIV-1 viral load and CD4+ T cell count [4]. It is also proposed that immune activation drives AIDS development in simian immunodeficiency virus (SIV) infected monkeys. In SIVinfected Asian monkeys (Rhesus macaques and pigtail macaques, e.g.) AIDS develops, associated with persistent immune activation and rapid CD4+ T-cell loss. In contrast, SIV infection of African monkeys (African Green monkeys and sooty mangabeys, e.g.) leads to no AIDS progression, correlated with only a transient and selflimiting immune activation despite similar levels of viral replication as pathogenic SIV infections [2,5,6]. In mice, repeated treatments with Toll like receptor (TLR)-9 [7] or TLR7 [8] ligands lead to AIDS-like immune dysregulation, correlated with immune activation and lymphoid organ destruction. In SIV-infected African green monkeys, treatment with lipopolysaccharide (LPS) results in CD4+ T-cell loss [9]. Finally, anti-inflammatory treatment with chloroquine [10] or hydroxychloroquine in combination with antivirals [11] inhibits immune activation in HIV-1 infected patients, correlated with elevated CD4+ T cells [11]. The mechanism by which HIV-1 infection leads to immune activation is not fully elucidated [2]. Several mechanisms have been proposed, including loss of gut tissue integrity and microbial products translocation [12] or persistent production of IFN-I [13,14]. Sustained IFN-I production is correlated with HIV-1 induced immune activation and disease progression both in HIV-1 infected patients [15] and pathogenic SIV infected monkey models Persistent expression of IFN-I is correlated with disease progression in HIV-1 infected humans or SIV-infected monkeys. Thus, persistent pDC activation has been implicated in contributing to AIDS pathogenesis. To define the role of pDC in HIV-1 infection and immunopathogenesis in vivo, we developed a monoclonal antibody that specifically and efficiently depletes human pDC in all lymphoid organs in humanized mice. We discover that pDC are the critical IFN-I producer cells in response to acute HIV-1 infection, because depletion of pDC completely abolished induction of IFN-I or ISG by HIV-1 infection, correlated with elevated level of HIV-1 replication. When pDC were depleted during chronic HIV-1 infection in humanized mice, pDC were still the major IFN-I producing cells in vivo, which contributed to HIV-1 suppression. Despite of higher level of viral replication in pDC-depleted mice, we found that HIV-induced depletion of human T cells and leukocytes was significantly reduced in lymphoid organs, correlated with reduced cell death induction by HIV-1 infection. Our findings demonstrate that pDC play two opposing roles in HIV-1 pathogenesis: they produce IFN-I to suppress HIV-1 replication and induce death of human immune cells to contribute to HIVinduced T cell depletion and immunopathogenesis. [16,17,18]. Although IFN-I inhibits HIV-1 replication in vitro [19], the high level IFN-I in HIV-1 patients is not correlated with viral control (...truncated)