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      Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections

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          Abstract

          The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4 + T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication.

          Author Summary

          Persistent activation of the immune system is a hallmark of chronic HIV/SIV infections and predicts disease progression better than either plasma viral load or CD4 + T cell count. While the causes of immune activation during chronic infection are likely multifactorial, recent work has shown that microbial translocation is associated with immune activation. However, direct, tissue level in vivo evidence of translocation and the underlying mechanisms remain unclear. Here, we sought direct in vivo evidence of translocation, and an understanding of the timing and the underlying mechanisms. We found that in RMs, microbial translocation begins during the late acute phase of SIV infection and increases progressively during chronic infection and is associated with structural damage of the GI tract. We further discovered that immune activation is temporally and causally related to microbial translocation and by the relative inability of intestinal macrophages to bind/phagocytose translocated microbial products. In SIV-infected sooty mangabeys, however, no evidence of epithelial barrier breakdown, nor increased microbial translocation or chronic immune activation were observed. Our results provide direct evidence for microbial translocation in vivo, coupled with early and progressive intestinal epithelial damage, and eventual impairment of macrophage clearance associated with dissemination of microbial products and systemic immune activation.

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          Most cited references41

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          Interleukin-18 regulates both Th1 and Th2 responses.

          Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-gamma. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglia. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.
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            Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells.

            In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system, is a principal site of both virus production and depletion of primarily lamina propria memory CD4+ T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT. Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells. Surprisingly, most of the initially infected memory cells were not, as expected, activated but were instead immunophenotypically 'resting' cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes, are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4+ T-cell targets to sustain infection, virus production also triggered an immunopathologically limiting Fas-Fas-ligand-mediated apoptotic pathway in lamina propria CD4+ T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4+ T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4+ T cells in the effector arm of GALT. The scale of this CD4+ T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.
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              Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia.

              HIV-infected humans and SIV-infected rhesus macaques who remain healthy despite long-term infection exhibit exceptionally low levels of virus replication and active antiviral cellular immune responses. In contrast, sooty mangabey monkeys that represent natural hosts for SIV infection do not develop AIDS despite high levels of virus replication and limited antiviral CD8(+) T cell responses. We report here that SIV-infected mangabeys maintain preserved T lymphocyte populations and regenerative capacity and manifest far lower levels of aberrant immune activation and apoptosis than are seen in pathogenic SIV and HIV infections. These data suggest that direct consequences of virus replication alone cannot account for progressive CD4(+) T cell depletion leading to AIDS. Rather, attenuated immune activation enables SIV-infected mangabeys to avoid the bystander damage seen in pathogenic infections and protects them from developing AIDS.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                August 2010
                August 2010
                19 August 2010
                : 6
                : 8
                : e1001052
                Affiliations
                [1 ]AIDS and Cancer Virus Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
                [2 ]Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America
                [3 ]Lab of Pathology, NCI, NIH, Bethesda, Maryland, United States of America
                [4 ]Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [5 ]Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland
                [6 ]Laboratory Animal Science Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
                [7 ]AdvanDX, Inc., Woburn, Massachusetts, United States of America
                [8 ]Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America
                [9 ]Center for Comparative Medicine, California National Primate Research Center, University of California, Davis, California, United States of America
                [10 ]Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America
                University of Zurich, Switzerland
                Author notes

                Conceived and designed the experiments: JDE DCD ATH JL JMB. Performed the experiments: JDE LDH NRK BT MP JS RP KMO JMB. Analyzed the data: JDE LDH NRK SP MP KMO VMH GS ATH JMB. Contributed reagents/materials/analysis tools: JDE MP GRB KMO GS CJM ATH JL. Wrote the paper: JDE JL JMB.

                Article
                09-PLPA-RA-2101R3
                10.1371/journal.ppat.1001052
                2924359
                20808901
                990faf47-677a-4a85-9bb0-bce04c6b6c98
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 18 November 2009
                : 20 July 2010
                Page count
                Pages: 15
                Categories
                Research Article
                Infectious Diseases/HIV Infection and AIDS

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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