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Subclinical endotoxemia has been reported in HIV-1 infected persons and may drive systemic immune activation and pathogenesis. ificantly increased LPS levels were associated with chronic HIV-1 infection, both treated and untreated, but not with other acute or semi-chronic conditions reported. Interestingly, the apparent in vivo tolerance effect was diminished in subjects with HIV infection. This is an open-access article distributed under the terms of the Creative Commons Attributionwhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The funders had no role in study de, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Lipopolysaccharide LPS or endotoxin is a component of Gram negative bacterial cell Lester Alabama woman sex and is known to induce large proinflammatory responses that cause bacterial sepsis [1]. Recently, increased levels of LPS have been found in the plasma of chronically HIV-1 infected individuals who did not demonstrate overt s of sepsis [2]. This has not, however, been explored in African populations where enteric microflora and opportunistic infections may be different and the HIV pandemic is at its peak.

Whatever the endotoxin source, subclinical endotoxemia could be Lester Alabama woman sex substantial driving force for chronic immune activation in HIV which has been linked to disease progression [5]. Microbes that invade the external physical barriers of mammalian hosts are recognized instantly by sensors of the innate immune system.

Toll-like receptors TLRfor instance, which are embedded in host immune cell membranes and intracellular compartments, recognize these microbial or pathogen associated molecular patterns PAMPs [6]. LPS was the prototypic proinflammatory microbial aling molecule shown to induce the mammalian Toll pathway [7]and the receptor was later identified as TLR4. Many human cell types express various TLR, especially those that have innate immune or barrier function.

Peripheral blood mononuclear cells PBMC are composed of circulating immune cells including lymphocytes, monocytes, and dendritic cells that are rich in TLR expression [11] and respond broadly to TLR ligands. We also identified a weak association between the increased TLR expression and plasma viral load, suggesting that viral products or viral replication may drive these TLR aling changes.

In this study, we sought to confirm the association between HIV infection and sub-clinical endotoxemia in a cohort of female sex-workers in Kenya, and evaluate TLR-mediated aling. All subjects gave informed written consent and were sampled during scheduled outpatient research visits. Routine questionnaires including data on clinical symptomatology, physician exam, and basic laboratory were collected on each visit.

All clinical investigation was conducted according to the principles of the Helsinki Declaration. Peripheral blood was collected by venipuncture. Cryopreserved plasmas, matched to our TLR study [13]were used in endotoxin assays. For new samples, peripheral blood mononuclear cells PBMCs Lester Alabama woman sex isolated from fresh blood by density gradient centrifugation as ly described [13] and were used fresh for in vitro culture studies or aliquotted and frozen in Trizol for TLR quantitative reverse-transcriptase real time PCR QRT-PCR.

Plasma LPS levels were then quantified using a commercially available Limulus Amebocyte assay Associates of Cape Cod and analyzed with background subtracted according to the package insert.

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The detailed protocol and TaqMan primers are published elsewhere [13]. Readout of data was a ratio of the gene quantity to its 18S rRNA quantity, defined as relative expression.

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Additional priming studies were carried out using lower dose of LPS 0. Post-prime media control assays ruled out ificant cytokine carry-over from initial TLR-ligand stimulations. Culture supernatants were diluted fold and assayed for cytokines using cytometric bead array BD Biosystems on a FACScan flow cytometer BD as per the manufacturers protocol.

Non-parametric tests were used including Mann-Whitney tests for comparing independent variables, Wilcoxon rank t -tests for paired samples, unpaired t tests for replicate experiments, and Spearman's rank test for matched correlations.

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Two tailed tests were used in all analyses. Study participant characteristics for direct ex vivo studies are shown in Table 1.

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Age and the level of sex-work activity were similar among these groups. However, there was substantive suppression of plasma HIV viral lo mean drop 1. Plasma endotoxin levels were frequently detectable by LAL in both HIV infected and uninfected subjects level of detection 0.

B HIV infected subjects were also more likely to have detectable LPS plasma levels than uninfected subjects Lester Alabama woman sex of detection 0. C Symptomatic clinical conditions suggestive of acute infectious etiologies were more frequent in HIV infected subjects than uninfected subjects. Endotoxin levels in acute symptomatic or physician diagnosed conditions during the study visits are shown in Figure 1C.

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In fact, a higher proportion of HIV infected subjects with detectable endotoxemia did not have symptoms compared to those that did not have detectable endotoxemia, though this was not statistically ificant. To summarize, in these women of high infection-risk, chronic HIV-1 Lester Alabama woman sex, whether treated or untreated, was associated with endotoxemia that was unassociated with acute presentation of illness. Since tolerance to endotoxin is important in preventing overwhelming inflammatory responses in advanced sepsis [15]decreased proinflammatory aling through chronic or repetitive endotoxin exposure is expected.

B In a similar pattern, overnight culture with 0. In short term in vitro culture, similar patterns of changes in TLR expression were seen. Comparison is by Mann-Whitney test. Considerable variability in cytokine response levels was seen between subjects and with various doses of LPS, but intra-subject responses were consistent. C The same experiment de but with reduced LPS levels to 0. Lowering the LPS dose to 0.

Between priming and the subsequent LPS stimulations, PBMCs were washed to remove solublized cytokines; and carry-over cytokines tested were negligible. All experiments were run in triplicate. Unpaired two tailed t tests were used. The data in these studies support that innate immune responses are fundamentally altered in HIV infection, which may influence chronic immune activation status and HIV disease.

Here, we confirmed, for the first time in an African setting, the association between chronic HIV infection and elevated plasma endotoxin levels. Interestingly, clinical symptoms or conditions that could indicate acute underlying infections where more frequent in HIV infected subjects, but asymptomatic HIV infected subjects were at Lester Alabama woman sex as likely to have high plasma endotoxin levels as those with symptoms or a diagnosed acute infection.

It is difficult from our study to determine the origin of plasma endotoxin in non-HIV infected subjects. On further review of the three HIV-uninfected subjects with the highest endotoxin levels, one had a skin abscess of which the causative agents are usually Gram positive, thus not LPS producingone had bacterial vaginosis which is non-invasive and unlikely to result in bacteremiaand the other had no identifiable illness at presentation. No other acute infectious etiologies were associated with detectable plasma endotoxin levels. Other underlying endemic infections such as with intestinal helminthes could be present and easily missed [17]however.

Additionally, vaginal douching with detergents is a common practice of sex-workers in Kenya [18]which could hypothetically disrupt the genital mucosa and affect microbial translocation at this site, though this has not been ly shown.

Further studies are required to assess the causes of subclinical endotoxemia in this and other populations, and Lester Alabama woman sex consistency of these findings over time. Immune Lester Alabama woman sex to overwhelming inflammatory stimuli, as seen in overt sepsis [19]is necessary to prevent circulatory collapse and death. In the case of chronic endotoxemia, little is known about immune control mechanisms. Here we show, for the first time, that chronic TLR4-mediated endotoxin tolerance is likely, since at the cusps of statistical ificance plasma endotoxin levels were associated with decreased TLR4 mRNA levels in peripheral blood, at least in HIV uninfected subjects.

This provided further evidence that HIV RNA was independently able to enhance the proinflammatory response to endotoxin. Interestingly, others have shown that LPS can drive HIV replication, even in the face of tolerized endotoxin responses [20]. Feedback TLR expression, as described here is one mechanism of immune regulation ly described [21]but other mechanisms exist [22][23]. Also, production of immune regulatory cytokine, IL, was Lester Alabama woman sex at higher levels in response to LPS than RNA40 in some subjects, but this was not observed in others.

Relative proportions of cell subsets may also contribute to relative TLR quantities and responsiveness. Further studies are warranted to delineate the TLR aling interactions in cellular subpopulations and tissue dependence of cross-TLR aling. Chronic immune activation is a strong predictor of HIV disease and death.

Meier et al. On the other hand, Brenchley and others suggested that microbial translocation and plasma endotoxemia are a cause of immune activation in HIV [24]. In this latter case, the source of inflammatory ligand is an indirect effect of HIV infection, and ART suppressive therapy appears to only gradually and partially lead to correction of the underlying process [25][26]. At this Lester Alabama woman sex that process is thought to be gastrointestinal mucosal integrity. Importantly, if microbial stimuli such as plasma LPS are drivers of immune activation and ultimately contribute to CD4 T cell decline and HIV disease, then viral suppressive therapy would only be expected to have limited or delayed affect on CD4 recovery and prevention of opportunistic infections.

In other words, the response to persistent endotoxemia could be dampened to normal or near normal levels. Indeed, many subjects respond with rapid immune reconstitution to ART, in a time frame unlikely to result from gastrointestinal mucosal repair, and may result in part from reduced innate immune dysregulation caused by circulating HIV RNA. New techniques have enabled the detection of minute quantities of diverse bacterial products in plasma and other typically sterile sites [26][27].

The precise mechanisms, extent and effects of microbial translocation in HIV are only starting to be worked out [25][28][29][30][31]. Similarly, innate immune changes in acute and chronic HIV infection are much less understood than their adaptive immune counterparts [32]. We would like to thank long standing participants of the Pumwani Sex-worker Cohort and dedicated clinic and laboratory staff.

Edited the paper: WRO. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Background Subclinical endotoxemia has been reported in HIV-1 infected persons and may drive systemic immune activation and pathogenesis. Introduction Lipopolysaccharide LPS or endotoxin is a component of Gram negative bacterial cell walls and is known to induce large proinflammatory responses that cause bacterial sepsis [1].

Sample acquisition and preparation Peripheral blood was collected by venipuncture. Increased plasma endotoxin levels are associated with HIV infection but not acute presenting conditions Study participant characteristics for direct ex vivo studies are shown in Table 1. Download: PPT.

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