Soluble Markers Of Immune Activation Research Articles

Structural Determinants of Health and Markers of Immune Activation and Systemic Inflammation in Sexual Minority Men With and Without HIV.

Among sexual minority men (SMM), HIV and use of stimulants such as methamphetamine are linked with immune activation and systemic inflammation. Throughout the COVID-19 pandemic, SMM encountered financial challenges and structural obstacles that might have uniquely contributed to immune dysregulation and systemic inflammation, beyond the impacts of HIV and stimulant use. Between August 2020 and February 2022, 72 SMM with and without HIV residing in South Florida enrolled in a COVID-19 prospective cohort study. Multiple linear regression analyses examined unemployment, homelessness, and history of arrest as structural correlates of soluble markers of immune activation (i.e., sCD14 and sCD163) and inflammation (i.e., sTNF-α receptors I and II) at baseline after adjusting for HIV status, stimulant use, and recent SARS-CoV-2 infection. Enrolled participants were predominantly Latino (59%), gay-identified (85%), and with a mean age of 38 (SD, 12) years with approximately one-third (38%) of participants living with HIV. After adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use, unemployment independently predicted higher levels of sCD163 (β = 0.24, p = 0.04) and sTNF-α receptor I (β = 0.26, p = 0.02). Homelessness (β = 0.25, p = 0.02) and history of arrest (β = 0.24, p = 0.04) independently predicted higher levels of sCD14 after adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use. Independent associations exist between structural barriers and immune activation and systemic inflammation in SMM with and without HIV. Future longitudinal research should further elucidate complex bio-behavioral mechanisms linking structural factors with immune activation and inflammation.

HIV-associated gut microbial alterations are dependent on host and geographic context

HIV-associated changes in intestinal microbiota are believed to be important drivers of disease progression. However, the majority of studies have focused on populations in high-income countries rather than in developing regions where HIV burden is greatest. To better understand the impact of HIV on fecal microbiota globally, we compare the fecal microbial community of individuals in the U.S., Uganda, and Botswana. We identify significant bacterial taxa alterations with both treated and untreated HIV infection with a high degree of uniqueness in each cohort. HIV-associated taxa alterations are also significantly different between populations that report men who have sex with men (MSM) behavior and non-MSM populations. Additionally, while we find that HIV infection is consistently associated with higher soluble markers of immune activation, most specific bacterial taxa associated with these markers in each region are not shared and none are shared across all three geographic locations in our study. Our findings demonstrate that HIV-associated changes in fecal microbiota are overall distinct among geographical locations and sexual behavior groups, although a small number of taxa shared between pairs of geographic locations warrant further investigation, highlighting the importance of considering host context to fully assess the impact of the gut microbiome on human health and disease.

CD4 dim CD8 bright T cells are inversely associated with neuro-inflammatory markers among people with HIV.

HIV-associated neuroinflammation persists in the brain despite suppressive combination antiretroviral therapy (cART). We evaluated associations between a subset of CD8 + T cells, termed CD4 dim CD8 bright T cells, and soluble markers of immune activation and/or neuroinflammation in the cerebrospinal fluid (CSF) and plasma of people with HIV (PWH). Fifteen cART-naive PWH were enrolled and underwent blood draw, lumbar puncture for CSF collection, and neuropsychological tests at week 0 (pre-cART) and 24 weeks after cART initiation. CSF and peripheral blood T cells were evaluated with flow cytometry and soluble markers of immune activation were measured by multiplex and singleplex assays. Spearman bootstrap correlation coefficients with 10 000 resamples were computed and reported with corresponding 95% confidence intervals (CIs) for each marker of interest and T-cell type. The frequency of CSF CD4 dim CD8 bright T cells at week 0 was inversely related with CSF neopterin. In contrast, at week 24, CSF CD4 - CD8 + T cells were positively correlated with CSF s100β, a marker of brain injury. In the blood, at week 0, CD4 dim CD8 bright T cells were inversely correlated with MCP-1, IP-10, IL-8, IL-6, G-CSF, and APRIL and positively correlated with plasma RANTES and MMP1. At week 0, the frequency of blood CD4 - CD8 + were positively correlated with CRP and BAFF. CD4 dim CD8 bright T cells are associated with some anti-inflammatory properties, whereas CD4 - CD8 + T cells may contribute to inflammation and injury. Assessing the contrast between these two cell populations in neuroHIV may inform targeted therapeutic intervention to reduce neuroinflammation and associated neurocognitive impairment.

Stimulant use, HIV, and immune dysregulation among sexual minority men

BackgroundSexual minority men (SMM) report high rates of stimulant use (e.g., crystal methamphetamine, cocaine) and HIV infection. Stimulant use contributes to immune dysfunction, which enhances risk for HIV acquisition and pathogenesis. Research is needed to examine the independent and interactive relationships of stimulant use and HIV infection with systemic immune dysregulation among SMM, especially during the COVID-19 pandemic. MethodsFrom 2020–2022, 75 SMM in Miami, Florida with and without HIV completed an online survey and provided biospecimens to assess HIV status and viral load (VL), recent stimulant use, and soluble markers of immune activation and inflammation in plasma, including soluble CD14 (sCD14) and elevated high-sensitivity C-reactive protein (hs-CRP > 1.0mg/L). Sociodemographics and prior SARS-CoV-2 infection were compared across HIV status/stimulant use groups. Moderation models examined the independent and interactive associations of stimulant use and HIV status with sCD14 and elevated hs-CRP. ResultsThirty participants were persons living with HIV (PWH) (50% with stimulant use), and 45 were HIV-negative (44% with stimulant use). SARS-CoV-2 infection was not associated with stimulant use/HIV groups or immune outcomes. HIV-negative SMM without stimulant use had lower sCD14 compared to other SMM, as well as lower odds of elevated hs-CRP compared to PWH who used stimulants. Stimulant use showed independent associations with immune dysregulation that persisted after controlling for HIV status and VL, whereas HIV status was only independently associated with elevated hs-CRP in one model not controlling for VL. ConclusionsAmong SMM, stimulant use was independently associated with elevated immune activation and inflammation.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

BackgroundElevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here.MethodsIn a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants.ResultsBefore therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy.ConclusionDuring chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

Plasma d-amino acids are associated with markers of immune activation and organ dysfunction in people with HIV

d-Amino acids (d-AAs) have been associated with age-associated conditions in the general population but their relevance in people with HIV (PWH), who experience accentuated/accelerated aging has not been studied. We compared d-AA levels in HIV-infected and uninfected controls and explored their association with markers of immune activation, gut permeability and organ dysfunction. Case-control analysis. Plasma samples from 60 antiretroviral therapy-treated HIV-infected individuals and 59 uninfected controls were analysed. A three-dimensional HPLC system was used to measure d-and l-asparagine, serine, alanine and proline and presented as %d-AA. Additionally, cell-associated and soluble markers of immune activation and senescence were characterized. Kidney and liver functions were expressed as estimated glomerular filtration rate and fibrosis-4 scores, respectively. Mann-Whitney and Spearman rank correlation coefficients were used for statistical analysis. d-Asparagine, d-serine, d-alanine and d-proline were detectable in all plasma samples and correlated with age in HIV-infected and uninfected but not different between groups. Kynurenine/tryptophan ratio was positively correlated with all %d-AAs in PWH and with %d-serine and %d-proline in controls. %d-AAs were not consistently correlated with markers of gut permeability in both groups. All %d-AAs were also correlated with kidney function in both groups whereas age-associated accumulation of %d-asparagine, %d-serine and %d-proline were correlated with liver function and the VACS score in controls. Plasma d-AAs are associated with chronological age and correlated with markers of immune activation and organ decline, though variably, in PWH and controls. Their role in the biology of aging warrants further investigation.

Chronic Immune Activation and CD4+ T Cell Lymphopenia in Healthy African Individuals: Perspectives for SARS-CoV-2 Vaccine Efficacy.

Chronic immune activation has been considered as the driving force for CD4+ T cell depletion in people infected with HIV-1. Interestingly, the normal immune profile of adult HIV-negative individuals living in Africa also exhibit chronic immune activation, reminiscent of that observed in HIV-1 infected individuals. It is characterized by increased levels of soluble immune activation markers, such as the cytokines interleukin (IL)-4, IL-10, TNF-α, and cellular activation markers including HLA-DR, CD-38, CCR5, coupled with reduced naïve and increased memory cells in CD4+ and CD8+ subsets. In addition, it is accompanied by low CD4+ T cell counts when compared to Europeans. There is also evidence that mononuclear cells from African infants secrete less innate cytokines than South and North Americans and Europeans in vitro. Chronic immune activation in Africans is linked to environmental factors such as parasitic infections and could be responsible for previously observed immune hypo-responsiveness to infections and vaccines. It is unclear whether the immunogenicity and effectiveness of anti-SARS-CoV-2 vaccines will also be reduced by similar mechanisms. A review of studies investigating this phenomenon is urgently required as they should inform the design and delivery for vaccines to be used in African populations.

The impact of integrase inhibitor-based regimens on markers of inflammation among HIV naïve patients

The use of combination anti-retroviral therapy (cART) correlates with longer and healthier life and with nearly normal life expectancy in people living with HIV. However, cART does not completely restore health. Chronic immune activation and inflammation persist in treated patients and have been described as predictors for clinical events and mortality in HIV-infected patients. Limited information is available on the impact of the various cART regimens on inflammation/immunoactivation. The aim of this work was to explore the impact of elvitegravir, dolutegravir, raltegravir (integrase strand transfer inhibitors, INSTIs) and atazanavir (protease inhibitor, PI) on several soluble markers of immune activation and inflammation during the first year of effective combination anti-retroviral therapy (cART).We conducted an observational retrospective cohort study in HIV-infected cART-naïve patients who initiated an INSTI or atazanavir regimen between March 2015 and February 2016 and a serum sample was available at baseline, 6 and 12 months after initiation. We compared the trend of D-Dimer, TNF- α, IL-2, IL-6, IL-7, IL-10, CCL4/MIP1-β, CCL5/RANTES, s-CD14, s-CD163, hs-CRP levels among the 4 arms of treatment. Percentage of variation from baseline was also measured for all markers.A total of 36 patients were included. We observed heterogeneous modifications in inflammation markers among arms. In particular, we noted that EVG have significant negative effect on s-CD14, hs-CRP, IL-6 and D-Dimer in respect to other INSTIs and this different effect occurs mainly during the first 6 months of cART. IL-7 values increased in the three arms with INSTIs (significantly only in EGV, 159.8%, p = 0.0003) and decreased significantly in patients on PI (−48.96%; p = 0.04) over the period.In conclusion, our results provide further data on changes of inflammatory marker levels, especially for the new INSTIs. Our data show that among INSTIs, EVG seems to have a worse impact on inflammation.

Soluble Markers of Immune Activation Differentially Normalize and Selectively Associate with Improvement in AST, ALT, Albumin, and Transient Elastography During IFN-Free HCV Therapy.

Background:During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evaluation of liver damage stage. While a portion of the TE score is attributable to liver fibrosis and relatively irreversible damage, another component of the TE score is attributable to liver inflammation or edema. Markers of inflammation during chronic HCV infection include soluble markers of immune activation, which are also associated with morbid outcome (including cardiovascular disease and liver-disease progression). Whether soluble markers of immune activation or changes in their level during HCV therapy relate to normalization of AST, ALT, Albumin, or TE score, is not clear.Methods:We evaluated soluble markers of immune activation (plasma sCD14, IL-6, sCD163, autotaxin [ATX], and Mac2BP) and TE score, and their relationship in 20 HCV-infected patients before, during, and after HCV-directed IFN-free direct-acting antiviral (DAA) therapy. We evaluated normalization of parameters and the relationship between each over a 6-month window.Results:Before therapy, serum AST levels positively correlated with plasma levels of sCD14, sCD163, and Mac2BP, while ALT levels positively correlated with Mac2BP. Serum albumin level negatively correlated with plasma IL-6 and ATX levels. IFN-free therapy uniformly resulted in sustained virological response at 12 and 24 weeks after therapy completion. After initiation of therapy AST and ALT normalized, while levels of ATX, Mac2BP, sCD163, and TE score partially normalized over 6 months. Additionally, change in AST level and APRI score correlated with change in sCD163, IL-6, and Mac2BP levels, and change in ALT correlated with change in IL-6 and Mac2BP levels. Improvement in TE score correlated with a decrease in the level of sCD14 at week 4, and almost statistically significant with decrease in sCD14 at weeks 20-24 after initiation of IFN-free HCV therapy.Conclusions:Soluble markers of immune activation normalize or partially normalize at different rates after initiation of curative HCV DAA therapy, and TE scores improve, with wide variability in the degree of absolute improvement in liver stiffness from patient to patient. Decline magnitude of sCD14 was associated with improvement in TE score, while magnitude of improvement in AST correlated with reduction in sCD163 levels. These data provide support for a model where monocyte/Kupffer cell activation may account for a portion of the liver inflammation and edema, which is at least partially reversible following initiation of HCV DAA therapy.

Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease.

Systemic immune activation is critical to the pathogenesis of HIV-1 disease, and is accentuated in HIV/TB co-infected patients. The contribution of immune activation at sites of HIV/TB co-infection to viral activity, CD4 T cell count, and productive HIV-1 infection remain unclear. In this study, we measured markers of immune activation both in pleural fluid and plasma, and in T cells in pleural fluid mononuclear cell (PFMC) and peripheral blood mononuclear cell (PBMC) in HIV/TB co-infected subjects. The relationship between soluble and T cell activation markers with viral load in pleural fluid and blood CD4 T cell count were assessed. The T cell phenotype and activation status of HIV-1 p24 + T cells in PFMC and PBMC from HIV/TB patients were determined. We found that T cell and macrophage-specific and non-specific soluble markers of immune activation, sCD27, sCD163, IL1Ra, and sCD14, were higher in pleural fluid as compared to plasma from HIV/TB co-infected subjects, and higher as compared to pleural fluid from TB mono-infected subjects. Intestinal fatty acid-binding protein, a marker of intestinal tract damage, in plasma from HIV/TB co-infected patients was not different than that in HIV+ subjects. Expression of HLADR and CD38 double positive (HLADR/CD38) on CD4 T cells, and CD69+ on CD8 T cells correlated with pleural fluid viral load, and inversely with blood CD4 T cell count. Higher expression of HLADR/CD38 and CCR5 on CD4 T cells, and HLADR/CD38 and CD69 on CD8 T cells in PFMC were limited to effector memory populations. HIV-1 p24+ CD8 negative (includes CD4 + and double negative T cells) effector memory T cells in PFMC had higher expression of HLADR/CD38, Ki67, and CCR5 compared to HIV-1 p24- CD8 negative PFMC. Cumulatively, these data indicate that sites of HIV/TB co-infection are the source of intense immune activation.

During Hepatitis C Virus (HCV) Infection and HCV-HIV Coinfection, an Elevated Plasma Level of Autotaxin Is Associated With Lysophosphatidic Acid and Markers of Immune Activation That Normalize During Interferon-Free HCV Therapy

Immune activation predicts morbidity during hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection, although mechanisms underlying immune activation are unclear. Plasma levels of autotaxin and its enzymatic product, lysophosphatidic acid (LPA), are elevated during HCV infection, and LPA activates immunocytes, but whether this contributes to immune activation is unknown. We evaluated plasma levels of autotaxin, interleukin 6 (IL-6), soluble CD14 (sCD14), soluble CD163 (sCD163), and Mac2 binding protein (Mac2BP) during HCV infection, HIV infection, and HCV-HIV coinfection, as well as in uninfected controls, before and after HIV antiretroviral therapy (ART) initiation and during interferon-free HCV therapy. We observed greater plasma autotaxin levels in HCV-infected and HCV-HIV-coinfected participants, compared with uninfected participants, primarily those with a higher ratio of aspartate aminotransferase level to platelet count. Autotaxin levels correlated with IL-6, sCD14, sCD163, Mac2BP, and LPA levels in HCV-infected participants and with Mac2BP levels in HCV-HIV-coinfected participants, while in HIV-infected individuals, sCD14 levels correlated with Mac2BP levels. Autotaxin, LPA, and sCD14 levels normalized, while sCD163 and Mac2BP levels partially normalized within 6 months of starting interferon-free HCV therapy. sCD163 and IL-6 levels normalized within 6 months of starting ART for HIV infection. In vitro, LPA activated monocytes. These data indicate that elevated levels of autotaxin and soluble markers of immune activation during HCV infection are partially reversible within 6 months of initiating interferon-free HCV treatment and that autotaxin may be causally linked to immune activation during HCV infection and HCV-HIV coinfection.

SIV Infection-Mediated Changes in Gastrointestinal Bacterial Microbiome and Virome Are Associated with Immunodeficiency and Prevented by Vaccination.

AIDS caused by simian immunodeficiency virus (SIV) infection is associated with gastrointestinal disease, systemic immune activation, and, in cross-sectional studies, changes in the enteric virome. Here we performed a longitudinal study of a vaccine cohort to define the natural history of changes in the fecal metagenome in SIV-infected monkeys. Matched rhesus macaques were either uninfected or intrarectally challenged with SIV, with a subset receiving the Ad26 vaccine, an adenovirus vector expressing the viral Env/Gag/Pol antigens. Progression of SIV infection to AIDS was associated with increased detection of potentially pathogenic viruses and bacterial enteropathogens. Specifically, adenoviruses were associated with an increased incidence of gastrointestinal disease and AIDS-related mortality. Viral and bacterial enteropathogens were largely absent from animals protected by the vaccine. These data suggest that the SIV-associated gastrointestinal disease is associated with the presence of both viral and bacterial enteropathogens and that protection against SIV infection by vaccination prevents enteropathogen emergence.

Immunologic, virologic, and pharmacologic characterization of the female upper genital tract in HIV-infected women.

: A comparative analysis of cellular and soluble markers of immune activation in HIV-infected women on combination antiretroviral therapy showed that the upper genital tract (UGT) compared to the lower female genital tract was characterized by higher frequencies of potential HIV target cells and increased inflammatory molecules. Despite the activated UGT milieu, HIV RNA could not be detected in paired samples of plasma, cervicovaginal or endometrial lavage. As antiretroviral concentrations were ≥3-fold higher in the endometrium than in the lower genital tract, high antiretroviral penetration and/or metabolism may limit viral replication in the UGT.

Behavioural, Mucosal and Systemic Immune Parameters in HIV-infected and Uninfected Injection Drug Users.

ObjectiveInjection drug use (IDU) remains a major risk factor for HIV-1 acquisition. The complex interplay between drug use, non-sterile injection, and Hepatitis C remains poorly understood. We conducted a pilot study to determine the effect of IDU on immune parameters among HIV-uninfected and -infected individuals. We hypothesized that IDU could further augment immunological changes associated with HIV-1 infection, which could in turn affect HIV pathogenesisMethodsHIV-uninfected and -infected subjects with IDU, and non-IDU controls were recruited to obtain socio-demographic and drug-related behaviours. Blood (PBMC) and mucosal (MMC) mononuclear cells were analysed for cellular markers of immune activation (CD38 and Ki67). Serum ELISA was performed to determine levels of soluble CD14, a marker of immune activation.ResultsNo significant quantitative differences in CD4+ and CD8+ T cell levels were observed between IDU and non-IDU subjects when accounting for the presence of HIV-1 infection. However, increased levels of cellular and soluble markers of immune activation were documented in cells and plasma of HIV-uninfected IDU subjects compared to non-injectors. Additionally, sharing of injection paraphernalia was related to immune activation among HIV-uninfected IDU subjects.ConclusionIDU, with or without HIV-1 infection, results in a significant increase in immune activation in both the peripheral blood and the GI tract. This may have significant impact on HIV transmission, pathogenesis, and immunologic responses to combination antiviral therapy. This study provides compelling preliminary results which in turn support larger studies to better define the relationship between IDU, infection with HIV-1, co-infection with Hepatitis C and immunity.

Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents.

Combination antiretroviral therapy initiated within several weeks of human immunodeficiency virus (HIV) infection in adults limits proviral reservoirs that preclude HIV cure. Biomarkers of restricted proviral reservoirs may aid in the monitoring of HIV remission or cure. To quantify peripheral blood proviral reservoir size in perinatally HIV-infected (PHIV+) adolescents and to identify correlates of limited proviral reservoirs. A cross-sectional study including 144 PHIV+ youths (median age, 14.3 years) enrolled in the United States-based Pediatric HIV/AIDS Cohort Study and receiving durable (median duration, 10.2 years) combination antiretroviral therapy, stratified by age at virologic control. The primary end point was peripheral blood mononuclear cell (PBMC) proviral load after virologic control at different ages. Correlations between proviral load and markers of active HIV production (ie, HIV-specific antibodies, 2-long terminal repeat circles) and markers of immune activation and inflammation were also assessed. Proviral reservoir size was markedly reduced in the PHIV+ youth who achieved virologic control before 1 year of age (4.2 [interquartile range, 2.6-8.6] copies per 1 million PBMCs) compared with those who achieved virologic control at 1 to 5 years of age (19.4 [interquartile range, 5.5-99.8] copies per 1 million PBMCs) or after 5 years of age (70.7 [interquartile range, 23.2-209.4] copies per 1 million PBMCs; P < .001). A proviral burden of less than 10 copies per 1 million PBMCs in PHIV+ youth was measured in 11 (79%), 20 (40%), and 13 (18%) participants with virologic control before 1 year, at 1 to 5 years, and after 5 years of age, respectively (P < .001). Lower proviral load was associated with undetectable 2-long terminal repeat circles (P < .001) and HIV-negative or indeterminate serostatus (P < .001) but not with concentrations of soluble immune activation markers CD14 and CD163. Early effective combination antiretroviral therapy with prolonged virologic suppression after perinatal HIV infection leads to negligible peripheral blood proviral reservoirs in adolescence and is associated with negative or indeterminate HIV serostatus. These findings highlight the long-term effect of early effective control of HIV replication on biomarkers of HIV persistence in perinatal infection and the utility of HIV serostatus as a biomarker for small proviral reservoir size, although not necessarily for cure.

Enhanced immune activation linked to endotoxemia in HIV-1 seronegative MSM.

This study assessed cellular and soluble markers of immune activation in HIV-1 seronegative MSM. MSM immune profiles were characterized by an increased expression of CD57 on T cells and endotoxemia. Endotoxin presence was linked to recent high-risk exposure and associated with elevated cytokine levels and decreased CD4+/CD8+ T cell ratios. Taken together, these data show elevated levels of inflammation linked to periods of endotoxemia resulting in a significantly different immune phenotype in a subset of MSM at a high risk of HIV-1 acquisition.

Serum-derived Bovine Immunoglobulin Isolate: A New Medical Food for the Clinical Dietary Management of Enteropathy

Purpose: The intestinal epithelial barrier is critical in maintaining gut homeostasis. The loss of structural and functional integrity of the intestinal epithelial barrier increases permeability, which can allow greater antigenic penetration and subsequent activation of mucosal immune responses. The related inflammatory responses can contribute to several gastrointestinal (GI) disorders or enteropathies. The clinical manifestations vary among enteropathies, though abdominal pain or discomfort, bloating, flatulence, and altered bowel habits are common. The complex interactions between immune and nervous systems with the gut require a multifactorial, pathophysiological approach rather than targeting a single receptor/effector pathway. Methods: A number of studies suggest a potential role for serum-derived bovine immunoglobulin/protein isolate (SBI) to provide distinct nutrition in enteropathies, which decrease absorption and utilization of specific nutrients, alongside traditional medications that target specific aspects of the disease. SBI is a prescription medical food, specially formulated to be consumed orally or enterally under the medical supervision for the dietary management of enteropathy. It is affirmed as generally recognized as safe with no FDA objections. SBI has been shown in various nonclinical and clinical studies to have multiple mechanisms of action. These include: neutralizes bacterial endotoxins, balances intestinal microbiota, maintains integrity of the tight junctions, reduces cellular and soluble markers of immune activation, increases anti-inflammatory markers, and improves intestinal barrier dysfunction affected by inflammation. Results: Non-clinical trials have confirmed that plasma proteins containing immunoglobulins affects cellular immune activation, resulting in improved intestinal mucosal barrier function, reduced inflammation and diarrhea, as well as improved dietary protein utilization. In a HIV clinical study, SBI has been reported to decrease loose or watery bowel movements and increase absorptive function. Early studies in patients with IBS-D, malnutrition, or HIV enteropathy have noted improvements in nutrient retention and GI symptoms. Conclusion: The nutritional therapeutic approach aimed at restoring the mucosal membrane homeostasis and inhibiting intestinal immune activation through multiple mechanisms may be beneficial in GI disorders. Non-clinical and clinical studies demonstrate that nutritional management with SBI facilitates the restoration of the intestinal epithelial barrier and immune activation, thereby managing GI symptoms and improving nutritional status. SBI may prove beneficial in the nutritional management of diseases associated with intestinal inflammation.

Enhanced tryptophan degradation in patients with ovarian carcinoma correlates with several serum soluble immune activation markers

Tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) represents an antimicrobial and antitumoral immune effector mechanism, but IDO also suppresses T-cell responses and thus can cause immune system failure. Therefore, IDO was proposed as an immunoescape mechanism of tumor cells. Compared to healthy controls, accelerated tryptophan degradation was observed in the blood of 20 patients with ovarian carcinoma as is reflected by an increased kynurenine to tryptophan ratio (kyn/trp) which allows an estimate of IDO activity. Higher FIGO stage but not tumor grading was associated with a higher rate of tryptophan degradation. Kyn/trp correlated strongly with concentrations of cytokine IL-6, of soluble interleukin-2 receptor-α and 75 kDa TNF-α receptor and of the macrophage marker neopterin (all p < 0.001 or p < 0.01) but not with TNF-α. Findings further supports the concept that increased IDO activity in ovarian cancer patients relates to immune activation pathways. Accordingly, accelerated tryptophan degradation appears to represent an immune escape mechanism. However IDO activity is not necessarily a spontaneous activity of ovarian cancer cells rather it is elicited by the activated immune system although an additional spontaneous activity of tumor cells cannot be ruled out.

Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression

Both T-cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown. To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression. Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection. The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set point 12 months postinfection and time taken for CD4 cell counts to fall below 350 cells/microl were determined using multivariate and Cox proportional hazards regression. We found that the concentrations of five plasma cytokines, IL-12p40, IL-12p70, IFN-gamma, IL-7 and IL-15 in women with acute infection predicted 66% of the variation in viral load set point 12 months postinfection. IL-12p40, IL-12p70 and IFN-gamma were significantly associated with lower viral load, whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and granulocyte-macrophage colony-stimulating factor during acute infection were associated with maintenance of CD4 cell counts above 350 cells/microl, whereas IL-1alpha, eotaxin and IL-7 were associated with more rapid CD4 loss. A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women.

Rifaximin For Preventing Acute Graft Versus Host Disease: Impact On Plasma Markers Of Inflammation And T Cell Activation

Abstract Abstract 4664 Translocation of commensal bacteria across the damaged gut mucosa is critical in the pathogenesis of acute graft versus host disease (AGVHD), promoting inflammation that primes donor T cells. Pre-clinical research has demonstrated that mitigating the effects of the gut flora prevents AGVHD, but preserves the graft versus leukemia effect of the transplant. Rifaximin is a very broadly acting, minimally absorbed oral antibiotic, which has been shown to be effective in inflammatory bowel disease. We conducted a pilot trial to test the hypothesis that rifaximin would abrogate systemic inflammation and resultant T cell activation in allogeneic transplant recipients. Twenty adult and pediatric (≥12 years) allogeneic (related or unrelated) blood and marrow transplant recipients with hematological malignancies were enrolled between January 2008 and May 2009. All patients received myeloablative conditioning. Rifaximin, 400 mg bid, was started on day -10 and continued through day 30. Enzyme-linked immunosorbent assays were performed on plasma samples obtained pre-transplant (as a baseline), day 0 (pre-transplant) and day 15 to measure changes in the levels of two markers of inflammation, soluble TNF receptor 1 (sTNFR1) and interleukin 6 (IL-6), and one marker of donor T cell activation, soluble IL-2 receptor (sIL-2R). A historical control group was formed from a previously conducted study (2006-2007) to assess the potential of soluble markers of immune activation to predict AGVHD. Of the 61 patients enrolled in that study, 24 met the criteria for the rifaximin trial and, thus, were selected as controls. There were no significant differences between the treatment and historical control groups in terms of conditioning regimen, the proportion of alternative donors or GVHD prophylaxis. The treatment group, however, was significantly younger (median age; 17.3 years vs. 38.8 years) and included significantly more unrelated cord blood transplant recipients (7 (3 single unit and 4 double unit) vs. 0, p=0.01). The mean percentage of doses of rifaximin that were successfully administered was 86.2%. There were no serious adverse events attributed to rifaximin. The cumulative incidences of grade 2-4 AGVHD, grade 3-4 AGVHD and stage 1-4 gastrointestinal AGVHD in the treatment group did not differ significantly from those of the historical control group (grade 2-4, treatment=69%, control=58%, p=0.63; grade 3-4, treatment=34%, control=22%, p=0.50; gastrointestinal, treatment=58%, control=45%, p=0.58). The median increase from baseline in the IL-6 level at day 0 was significantly lower for the treatment group (table 1). Otherwise, there was no other significant difference in measured biomarker levels. Controlling for age by stratified analysis, and excluding the cord blood transplants did not alter our results. The results of this pilot study demonstrate that administering rifaximin to prevent AGVHD is safe and feasible. Its effect on systemic inflammation, though, appears to be modest and insufficient to mitigate activation of donor T cells. It, therefore, may not be suitable for GVHD prophylaxis. Table 1 . Median change in biomarker level from baseline Treatment Historical Controls p-value * IL-6 (pg/ml) Day 0 0.0 0.2 0.02 Day 15 7.9 9.6 0.61 TNFR1 (pg/ml) Day 0 379 438 0.92 Day 15 1555 1467 0.82 sIL-2R (ng/ml) Day 15 14.6 5.0 0.21 * Wilcoxon rank sum test Horan Salix Pharmaceuticals: Research Funding, investigator initiated clinical trial . Disclosures: Off Label Use: Rifaximin is an oral non-absorbable antibiotic that is approved for the treatment of travelers' diarrhea. In this study we investigate the use of Rifaximin for prophylaxis of acute graft versus host disease.