Differences in immune activation were identified as the most significant difference between AIDS-susceptible and resistant species. p38 MAPK, activated in HIV infection, is key to induction of ...interferon-stimulated genes and cytokine-mediated inflammation and is associated with some of the pathology produced by HIV or SIV infection in AIDS-susceptible primates. As small molecule p38 MAPK inhibitors are being tested in human trials for inflammatory diseases, we evaluated the effects of treating SIV-infected macaques with the p38 MAPK inhibitor PH-797804 in conjunction with ART. PH-797804 had no side effects, did not impact negatively the antiviral immune response and, used alone, had no significant effect on levels of immune activation and did not reduced the viremia. When administered with ART, it significantly reduced numerous immune activation markers compared to ART alone. CD38+/HLA-DR+ and Ki-67+ T-cell percentages in blood, lymph node and rectal CD4+ and CD8+ T cells, PD-1 expression in CD8+ T cells and plasma levels of IFNα, IFNγ, TNFα, IL-6, IP-10, sCD163 and C-reactive protein were all significantly reduced. Significant preservation of CD4+, CD4+ central memory, CD4+/IL-22+ and CD4+/IL-17+ T-cell percentages and improvement of Th17/Treg ratio in blood and rectal mucosa were also observed. Importantly, the addition of PH-797804 to ART initiated during chronic SIV infection reduced immune activation and restored immune system parameters to the levels observed when ART was initiated on week 1 after infection. After ART interruption, viremia rebounded in a similar fashion in all groups, regardless of when ART was initiated. We concluded that the inhibitor PH-797804 significantly reduced, even if did not normalized, the immune activation parameters evaluated during ART treatment, improved preservation of critical populations of the immune system targeted by SIV, and increased the efficacy of ART treatment initiated in chronic infection to levels similar to those observed when initiated in acute infection but did not affect positively or negatively viral reservoirs.
•Low accuracy of conventional testing complicates clinical management of urogenital tuberculosis.•Xpert demonstrates promising diagnostic efficiency for urogenital tuberculosis.•Xpert performance may ...not be affected by differing characteristics of included studies.•Integrating traditional tests with Xpert assay may increase likelihood of urogenital tuberculosis detection.
Effective methods for diagnosing urogenital tuberculosis (UGTB) are important for its clinical management. Therefore, we undertook a systematic review to assess the performance of the urine-based Xpert MTB/RIF assay for UGTB.
PubMed, Embase, Web of Science, the Cochrane library, and Scopus were systematically searched up to July 30, 2019. A hierarchical summary receiver operating characteristic (HSROC) was applied to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and odds ratio (OR) for the diagnostic accuracy of the Xpert test.
Our search identified 858 unique articles from which 69 studies were selected for full-text revision, with 12 studies meeting the inclusion criteria. Eleven studies comprising 1202 samples compared Xpert with mycobacterial culture, while 924 samples from eight studies compared it with a composite reference standard (CRS). The values for pooled sensitivity, specificity, PLR, NLR, and OR were 0.89, 0.95, 20.1, 0.18, and 159.53, respectively, when compared with the mycobacterial culture. Likewise, when compared with a CRS, the respective pooled sensitivity, specificity, PLR, NLR, and OR values were 0.55, 0.99, 40.67, 0.43, and 166.17, thereby suggesting a high level of accuracy for diagnosing UGTB. A meta-regression and sub-group analysis of TB-burden countries, study design, decontamination, concentration, and reference standard could not explain the heterogeneity (p > 0.05) in the diagnostic efficiency.
Our results suggested that Xpert is a promising diagnostic tool for the diagnosis of UGTB via urine specimen.
Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in ...less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (
= 20) and progressors (
= 18). Eight of these progressors were followed up at 6-12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.
BackgroundCD8+ T cells are critical components of the immune reaction against viral infections and cancer and have the potential to eliminate infected or malignant cells. However, when the antigen ...persists, CD8+ T cells enter an exhausted state. Chronic disease can lead to increased systemic noradrenaline (NA) levels, but it is currently still unclear how NA impacts the differentiation and function of exhausted CD8+ T cells. We here set out to characterize the effects of β adrenergic signaling on CD8+ T cells in chronic viral infection with LCMV-clone 13 and in murine cancer models.MethodsWe used multiparameter flow cytometry, single cell RNA sequencing, immunofluorescence microscopy, a conditional genetic knockout model as well as pharmacological inhibition of adrenergic receptors with FDA-approved drugs to profile the effects of β adrenergic signaling on CD8+ T cells.ResultsWe observed that chronically infected mice had elevated systemic NA levels and CD8+ T cells expressed higher levels of the β-1 adrenergic NA receptor, Adrb1. NA impaired T cell receptor signaling of ADRB1-expressing CD8+ T cells, and reduced T cell proliferation and function. Conversely, genetic ablation of ADRB1 prevented terminal CD8+ T cell differentiation in chronic viral infection and ADRB1-blockade enhanced T cell functionality in combination with immune checkpoint blockade (ICB) in an ICB-sensitive melanoma model. Expanding these observations to an ICB-resistant model of pancreatic cancer, we found that pharmacological blockade of adrenergic receptors synergized with ICB to genetically reprogram CD8+ T cells towards a tissue resident memory T cell-like state and improved T cell functionality, resulting in decreased tumor size.ConclusionsIn summary, our data suggest that β adrenergic receptors represent a novel immune checkpoint that modulates CD8+ T cell differentiation and function in the context of chronic antigen exposure and that targeting adrenergic receptors may synergize with ICB in cancer patients.Ethics ApprovalAnimals were housed in specific-pathogen-free facilities at the Salk Institute and all experimental studies were approved and performed in accordance with guidelines and regulations implemented by theSalk Institute Animal Care and Use Committee (IACUC number 17–00032).
BackgroundPeople living with HIV (PLWH) have increased risk of developing cancers after controlling traditional risk factors and viral suppression. This study explores whether T cells can serve as a ...marker of risk for cancer among HIV-infected virally suppressed patients.MethodsA nested case control study design was pursued with 17 cancer cases and 73 controls (PLWH without cancer)ouidentified among the US Military HIV Natural History Study cohort, and were matched for CD4 + count, duration of HIV infection, and viral suppression. Cells were obtained from PLWH on an average of 12 months prior to clinical cancer diagnosis. Expression of inhibitory receptors (PD-1, CD160, CD244, Lag-3, and TIGIT), and transcription factors (T-bet, Eomesodermin, TCF-1, and (TOX) was measured on CD8 +T cells from that early time point.ResultsWe found that cases have increased expression of PD-1 +CD160+CD244+ (‘triple positive’) on total and effector CD8 + compared with controls (p=0.02). Furthermore, CD8 +T cells that were both PD-1 +CD160+CD244+ and T-betdimEomeshi were significantly elevated in cases at time point before cancer detection, compared with controls without cancer (p=0.008). This was driven by the finding that transcriptional factor profile of cells was altered in cancers compared with controls. Triple-positive cells were noted to retain the ability for cytotoxicity and cytokine secretion mediated by expression of CD160 and PD-1, respectively. However, triple-positive cells demonstrated high expression of TOX-1, a transcription factor associated with T cell exhaustion.ConclusionIn conclusion, we have found a subset of dysfunctional CD8 +T cells, PD-1 +CD160+CD244+T-betdimEomeshi, that is elevated 12 months before cancer diagnosis, suggesting that peripheral T cell alterations may serve as a biomarker of increased cancer risk among PLWH.
Rice is one of the most popular staple foods produced contributing higher most in agriculture gross domestic production in Nepal. Thus, nutritional, physicochemical, and cooking properties of rice ...might interplay important roles in their production and farming practice, therefore, it is inevitable to understand these characteristic features. However, there has been only limited information available on such properties, therefore we aimed to examine nutritional, physicochemical and cooking properties of four Basmati varieties of rice namely Red Basmati, White Basmati, Black Basmati and Pokhareli Basmati. These rice varieties were purchased from different places in Nepal in paddy form. In this study various parameters associated with milling, nutritional, physical and cooking properties were evaluated. To measure protein contents in rice, Kjeldal method was implied. Among the varieties, the protein content was maximum in Red Basmati (7.74%) and minimum in Black Basmati (6.51%). The milled rice percentage and head rice recovery were maximum in Pokhareli Basmati represented by 72.02±0.10 and 67.46±0.42, respectively, while and minimum in White Basmati represented by 68.17±0.50 and 65.11±0.28, respectively. The kernel elongation ratio and volume expansion ratio was maximum in Red Basmati represented by 1.62 and 2.85 respectively. Water uptake ratio was maximum 3.11 in Black Basmati and minimum of 2.18 in Red Basmati. Gruel loss was found lowest 1.05% in Red Basmati and highest represented by 2.40% in Black Basmati. The highest starch iodine blue value of 0.21 was observed in Red Basmati and lowest of 0.12 in Black Basmati. The Red Basmati was found to have the better cooking quality among all varieties.
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) ...respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
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•The tumor microenvironment is enriched with lipids and oxidized lipids•Dysfunctional CD8+ TILs increase CD36 expression and OxLDL uptake•OxLDL uptake via CD36 inhibits T cell effector functions through lipid peroxidation•GPX4 overexpression promotes CD8+ TIL functionality
Lipid accumulation is a common metabolic alteration in the tumor microenvironment. Xu et al. show that intratumoral CD8+ T cells adapt to increased lipid concentrations by increasing expression of the scavenger receptor CD36. This, in turn, leads to intracellular accumulation of oxidized lipid and T cell dysfunction downstream of lipid peroxidation.
•Significantly lower expression of RCAs CR3 and CD46 on dendritic cell subsets of ART naïve HIV-1 infected individuals than healthy donors.•Significantly higher complement activation and plasma ...cytokine levels observed in treatment naïve HIV-1 infected individuals than controls.•Significantly lower plasma levels of cytokines were observed in treated vs. naïve HIV-1 infected individuals.•Modulation of CR3 and CD46 expression on DCs may influence HIV-1 infection and disease progression.
During infection and budding, human immunodeficiency virus-1 (HIV-1) acquires regulators of Complement Activation (RCAs) along with the host cell membrane on the viral envelope. Activation of host complement system results in opsonization of virus by complement fragments, however the virus evades complement mediated lysis (CoML) by virtue of the RCAs on the viral envelope. The RCAs on HIV-1 envelope process complement protein C3 into various fragments that promote viral entry and infection of cells through different complement receptors. Complement opsonized HIV-1 has been shown in vitro to infect dendritic cells (DCs) in a CR3 dependent manner, although the role of CR3 and CD46 in natural HIV-1 infection is not clear. Surface expression of CR3 and CD46 on DC subsets of 30 antiretroviral naïve, 31 treated (cART) HIV-1 infected individuals and 30 seronegative controls was measured by flow cytometry and plasma levels of cytokines and complement activity (C3c levels) were quantitated by sandwich ELISA. Significantly lower surface expression of CR3 and CD46 was observed on DC subsets in naïve and treated HIV-1 infected individuals compared to controls. Significantly higher complement activation and plasma levels of IL-4, IL-8, IL-10 and IFN-γ were observed in treatment naïve HIV-1 infected individuals than controls. Significantly lower plasma levels of IL-4, IL-6, IL-8 and IL-10 were observed in treated vs. naïve HIV-1 infected individuals. Our findings suggest that alterations in expression of CR3 and CD46 on DCs along with complement activity could be factors that influence viral persistence and HIV-1 disease progression and need to be further evaluated.
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