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      Glycerol monolaurate prevents mucosal SIV transmission

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          Abstract

          While there has been great progress in treating HIV-1 infection 1, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission 24. Nonetheless, studies of vaginal transmission in the SIV-rhesus macaque model point to opportunities in the earliest stages of infection where a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry 5, 6. Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α, plasmacytoid dendritic cells and CCR5+cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruit CD4+T cells to fuel this obligate expansion. We then show that glycerol monolaurate, a widely used antimicrobial compound 7 with inhibitory activity against production of MIP-3α and other proinflammatory cytokines 8, can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This novel approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for development of effective interventions to block HIV-1 mucosal transmission.

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          Most cited references 26

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          Plasmacytoid dendritic cells in immunity.

          Human and mouse plasmacytoid dendritic cells have been shown to correspond to a specialized cell population that produces large amounts of type I interferons in response to viruses, the so-called natural interferon-producing cells. As a result, intensive investigation is now focused on the potential functions of plasmacytoid dendritic cells in both innate and adaptive immunity. Here we review recent progress on the characterization of plasmacytoid dendritic cell origin, development, migration and function in immunity and tolerance, as well as their effect on human diseases.
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            Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection.

            It has recently been established that both acute human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are accompanied by a dramatic and selective loss of memory CD4+ T cells predominantly from the mucosal surfaces. The mechanism underlying this depletion of memory CD4+ T cells (that is, T-helper cells specific to previously encountered pathogens) has not been defined. Using highly sensitive, quantitative polymerase chain reaction together with precise sorting of different subsets of CD4+ T cells in various tissues, we show that this loss is explained by a massive infection of memory CD4+ T cells by the virus. Specifically, 30-60% of CD4+ memory T cells throughout the body are infected by SIV at the peak of infection, and most of these infected cells disappear within four days. Furthermore, our data demonstrate that the depletion of memory CD4+ T cells occurs to a similar extent in all tissues. As a consequence, over one-half of all memory CD4+ T cells in SIV-infected macaques are destroyed directly by viral infection during the acute phase-an insult that certainly heralds subsequent immunodeficiency. Our findings point to the importance of reducing the cell-associated viral load during acute infection through therapeutic or vaccination strategies.
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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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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                23 March 2009
                4 March 2009
                23 April 2009
                30 November 2009
                : 458
                : 7241
                : 1034-1038
                Affiliations
                [1 ] Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA
                [2 ] AIDS and Cancer Virus Program, Science Applications International Corporation–Frederick, Inc., National Cancer Institute, Frederick, Maryland, USA
                [3 ] Division of Biostatistics, School of Public Health, University of Minnesota, MMC 303, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA
                [4 ] Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 2001 6 th Street S.E., Minneapolis, Minnesota 55455, USA
                [5 ] Wisconsin National Primate Research Center, University of Wisconsin, 1220 Capitol Court, Madison, Wisconsin 53715, USA
                [6 ] Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, MMC 76, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA
                [7 ] Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, 200 Union Street S.E., Minneapolis, Minnesota 55455, USA
                Author notes
                Correspondence should be addressed to A.T.H. ( haase001@ 123456umn.edu )
                Article
                nihpa103040
                10.1038/nature07831
                2785041
                19262509
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Center for Research Resources : NCRR
                Award ID: R21 AI071976-02 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Center for Research Resources : NCRR
                Award ID: P51 RR000167-46S27592 ||RR
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Center for Research Resources : NCRR
                Award ID: P51 RR000167-440189 ||RR
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Center for Research Resources : NCRR
                Award ID: P51 RR000167-440109 ||RR
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Center for Research Resources : NCRR
                Award ID: P01 AI066314-040003 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Center for Research Resources : NCRR
                Award ID: G20 RR022780-01A1 ||RR
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