Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301-1309

Viral Immunobiology Laboratory, Molecular and Integrative Neuroscience Department, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature Medicine (Impact Factor: 27.36). 12/2006; 12(11):1301-9. DOI: 10.1038/nm1492
Source: PubMed


Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.

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Available from: Dorian McGavern, Oct 28, 2014
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    • "Chronic infection of lymphocytic choriomeningitis virus (LCMV) in mice leads to increased IL-10 production, especially by dendritic cells, resulting in continued PD-1 expression on T cells [39] [41]. IL-10 signalling blockade by administration of anti-IL10R antibodies intraperitoneally facilitates eradication of chronic LCMV infection [39] [41]. Similarly, IL- 10R blockade prevents mouse cytomegalovirus (MCMV) persistence [2]. "
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    ABSTRACT: Interleukin 10 is a cytokine with the ability to reduce or terminate inflammation. Chronic viral infection, such as infection of chronic hepatitis B, hepatitis C and HIV, has increased levels of interleukin 10 in peripheral blood. Serum IL-10 levels are also high in certain cancers. Blocking IL-10 signalling at the time of immunisation clears chronic viral infection and prevents tumour growth in animal models. We review recent advances in this area, with the emphasis on potential use of this novel strategy to treat chronic viral infection and cancer in human. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cellular Immunology 01/2015; 293(2):126-129. DOI:10.1016/j.cellimm.2014.12.012 · 1.92 Impact Factor
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    • "It is likely that the activation state of CD16+ monocytes accounts for this lower production of an immunoregulatory cytokine such as IL-10. The blockade of PD-1/PD-L1 interactions restores the immune response during HIV infection [17], [37]. Several evidence support that IL-10 and PD-1 constitute an amplification loop leading to immune impairment. "
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    ABSTRACT: Q fever endocarditis, a severe complication of Q fever, is associated with a defective immune response, the mechanisms of which are poorly understood. We hypothesized that Q fever immune deficiency is related to altered distribution and activation of circulating monocyte subsets. Monocyte subsets were analyzed by flow cytometry in peripheral blood mononuclear cells from patients with Q fever endocarditis and controls. The proportion of classical monocytes (CD14+CD16- monocytes) was similar in patients and controls. In contrast, the patients with Q fever endocarditis exhibited a decrease in the non-classical and intermediate subsets of monocytes (CD16+ monocytes). The altered distribution of monocyte subsets in Q fever endocarditis was associated with changes in their activation profile. Indeed, the expression of HLA-DR, a canonical activation molecule, and PD-1, a co-inhibitory molecule, was increased in intermediate monocytes. This profile was not restricted to CD16+ monocytes because CD4+ T cells also overexpressed PD-1. The mechanism leading to the overexpression of PD-1 did not require the LPS from C. burnetii but involved interleukin-10, an immunosuppressive cytokine. Indeed, the incubation of control monocytes with interleukin-10 led to a higher expression of PD-1 and neutralizing interleukin-10 prevented C. burnetii-stimulated PD-1 expression. Taken together, these results show that the immune suppression of Q fever endocarditis involves a cross-talk between monocytes and CD4+ T cells expressing PD-1. The expression of PD-1 may be useful to assess chronic immune alterations in Q fever endocarditis.
    PLoS ONE 09/2014; 9(9):e107533. DOI:10.1371/journal.pone.0107533 · 3.23 Impact Factor
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    • "This would be a study worth carrying out in sub-Saharan African population. Recently, the immunoregulatory cytokine IL-10 was identified as playing a key role in suppressing antiviral immune responses, leading to viral persistence [34] [35]. A study in South Africa populations indicated that individuals carrying the IL-10- 592AA genotype were more likely to become HIV-1 infected further; these results generally suggested that IL-10 promoter polymorphisms were linked to low IL-10 production and associated with increased HIV-1 susceptibility [36]. "
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    ABSTRACT: Sub-Saharan Africa has continued leading in prevalence and incidence of major infectious disease killers such as HIV/AIDS, tuberculosis, and malaria. Epidemiological triad of infectious diseases includes susceptible host, pathogen, and environment. It is imperative that all aspects of vertices of the infectious disease triad are analysed to better understand why this is so. Studies done to address this intriguing reality though have mainly addressed pathogen and environmental components of the triad. Africa is the most genetically diverse region of the world as well as being the origin of modern humans. Malaria is relatively an ancient infection in this region as compared to TB and HIV/AIDS; from the evolutionary perspective, we would draw lessons that this ancestrally unique population now under three important infectious diseases both ancient and exotic will be skewed into increased genetic diversity; moreover, other evolutionary forces are also still at play. Host genetic diversity resulting from many years of malaria infection has been well documented in this population; we are yet to account for genetic diversity from the trio of these infections. Effect of host genetics on treatment outcome has been documented. Host genetics of sub-Saharan African population and its implication to infectious diseases are an important aspect that this review seeks to address.
    08/2014; 2014(108291). DOI:10.1155/2014/108291
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