epiglucan and HIV-Infections

The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly

Topics: beta-Glucans; Biomarkers; Cross-Sectional Studies; HIV Infections; Humans

The intestinal epithelial layer serves as a physical and functional barrier between the microbiota in the lumen and immunologically active submucosa. Th17 T-cell function protects the gut epithelium from aggression from microbes and their by-products. Loss of barrier function has been associated with enhanced translocation of microbial products which act as endotoxins, leading to local and systemic immune activation. Whereas the inflammatory role of LPS produced by Gram-negative bacteria has been extensively studied, the role of fungal products such as β-D-glucan remains only partially understood. As HIV infection is characterized by impaired gut Th17 function and increased gut permeability, we critically review mechanisms of immune activation related to fungal translocation in this viral infection. Additionally, we discuss markers of fungal translocation for diagnosis and monitoring of experimental treatment responses. Targeting gut barrier dysfunction and reducing fungal translocation are emerging strategies for the prevention and treatment of HIV-associated inflammation and may prove useful in other inflammatory chronic diseases.

Topics: Animals; beta-Glucans; Biomarkers; Fungi; Gastrointestinal Microbiome; HIV Infections; Host-Pathogen Interactions; Humans; Intestinal Mucosa; Killer Cells, Natural; Microbial Viability; Models, Animal; Permeability

Immune activation is the driving force behind the occurrence of AIDS and non-AIDS events, and is only partially reduced by antiretroviral therapy (ART). Soon after HIV infection, intestinal CD4+ T cells are depleted leading to epithelial gut damage and subsequent translocation of microbes and/or their products into systemic circulation. Bacteria and fungi are the two most abundant populations of the gut microbiome. Circulating lipopolysaccharide (LPS) and (1→3)-β-D-Glucan (βDG), major components of bacterial and fungal cell walls respectively, are measured as markers of microbial translocation in the context of compromised gut barriers. While LPS is a well-known inducer of innate immune activation, βDG is emerging as a significant source of monocyte and NK cell activation that contributes to immune dysfunction. Herein, we critically evaluated recent literature to untangle the respective roles of LPS and βDG in HIV-associated immune dysfunction. Furthermore, we appraised the relevance of LPS and βDG as biomarkers of disease progression and immune activation on ART. Understanding the consequences of elevated LPS and βDG on immune activation will provide insight into novel therapeutic strategies against the occurrence of AIDS and non-AIDS events.

Topics: AIDS Dementia Complex; Anti-HIV Agents; Bacteria; Bacterial Translocation; beta-Glucans; Biomarkers; Cardiovascular Diseases; CD4-Positive T-Lymphocytes; Cell Wall; Disease Progression; Forecasting; Fungi; Gastrointestinal Microbiome; HIV Infections; Humans; Inflammation; Intestinal Mucosa; Lipopolysaccharides; Lymphocyte Activation; Models, Immunological; Proteoglycans

People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualise and culture fungi before initiating treatment. Such techniques are less practical in resource-limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)-β-d-glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV-infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels.

Topics: beta-Glucans; Diagnostic Tests, Routine; Drug Monitoring; HIV Infections; Humans; Invasive Fungal Infections; Proteoglycans

Using the evidence published over the last 2 years, this review discusses the epidemiology, diagnosis, treatment and prevention of HIV-related pulmonary infections other than mycobacterial disease.. Longstanding, vertically acquired and apparently stable HIV infection is associated with significant and symptomatic small airways disease in African adolescents. The use of population-based pneumococcal vaccination in children is changing the severity and serotypes associated with HIV-related pneumococcal disease. Data on the use of blood 1,3,β-D-glucan show it has promise as a rule-out test for Pneumocystis pneumonia (PCP).. With widespread antiretroviral medication usage, the pattern of HIV-associated pulmonary disease is changing. Whereas opportunistic infections such as PCP still occur in people not using antiretroviral therapy (ART), HIV-related infections are similar to those present in the general population. Chronic lung disease is more prevalent, leading to its own infectious complications. The use of specific immunizations against infections is important, though their precise benefit with concomitant widespread ART and population-based vaccination programmes in the non-HIV community is undetermined.

Topics: AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; beta-Glucans; HIV Infections; Humans; Lung Diseases; Pneumococcal Infections; Respiratory Tract Infections

1,3-β-Glucans are a class of natural polysaccharides with unique pharmacological properties and the ability to form single- and triple-helical structures that can be formed into resilient gels with the application of heat and humidity. The pharmacological capabilities of 1,3-β-glucans include the impartation of tumor inhibition, resistance to infectious disease, and improvements in wound healing. Curdlan is a linear 1,3-β-glucan that has been used extensively to study the nature of these helical structures and gels, and Curdlan sulfates have found ongoing application in the inhibition of HIV infection. 1,3-β-Glucan gels have been used in food science as stabilizers and encapsulating agents, in nanoscience as scaffolds to build nanofibers and nanowires, and in drug delivery to form nanoparticles and create helical micelles encapsulating polynucleotides. 1,3-β-Glucans are beginning to have enormous significance due to their dual nature as structure-forming agents and pharmacological substances, and research is especially focused on the application of these polymers in animal nutrition and drug delivery.

Topics: Animals; Anti-Infective Agents; Anticarcinogenic Agents; beta-Glucans; Carbohydrate Conformation; Drug Delivery Systems; Gels; HIV Infections; Hot Temperature; Humans; Immunologic Factors; Molecular Structure; Polysaccharides, Bacterial; Wound Healing

During the past 30 years, major advances have been made in our understanding of HIV/AIDS and Pneumocystis pneumonia (PCP), but significant gaps remain. Pneumocystis is classified as a fungus and is host-species specific, but an understanding of its reservoir, mode of transmission, and pathogenesis is incomplete. PCP remains a frequent AIDS-defining diagnosis and is a frequent opportunistic pneumonia in the United States and in Europe, but comparable epidemiologic data from other areas of the world that are burdened with HIV/AIDS are limited. Pneumocystis cannot be cultured, and bronchoscopy with bronchoalveolar lavage is the gold standard procedure to diagnose PCP, but noninvasive diagnostic tests and biomarkers show promise that must be validated. Trimethoprim-sulfamethoxazole is the recommended first-line treatment and prophylaxis regimen, but putative trimethoprim-sulfamethoxazole drug resistance is an emerging concern. The International HIV-associated Opportunistic Pneumonias (IHOP) study was established to address these knowledge gaps. This review describes recent advances in the pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP and ongoing areas of clinical and translational research that are part of the IHOP study and the Longitudinal Studies of HIV-associated Lung Infections and Complications (Lung HIV).

Topics: Adrenal Cortex Hormones; AIDS-Related Opportunistic Infections; Anti-Infective Agents; beta-Glucans; Biomarkers; Bronchoalveolar Lavage; Bronchoscopy; CD4 Lymphocyte Count; Dihydropteroate Synthase; Drug Resistance, Fungal; HIV Infections; Humans; Mutation; Pneumocystis carinii; Pneumonia, Pneumocystis; Pneumothorax; Polymerase Chain Reaction; Primary Prevention; Radiography, Thoracic; S-Adenosylmethionine; Secondary Prevention; Tetrahydrofolate Dehydrogenase; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

Maitake (Grifola frondosa) is the Japanese name for an edible fungus with a large fruiting body characterized by overlapping caps. It is a premier culinary as well as medicinal mushroom. Maitake is increasingly being recognized as a potent source of polysaccharide compounds with dramatic health-promoting potential. The most recent development is the MD-fraction, a proprietary maitake extract its Japanese inventors consider to be a notable advance upon the preceding D-fraction. The D-fraction, the MD-fraction, and other extracts, often in combination with whole maitake powder, have shown particular promise as immunomodulating agents, and as an adjunct to cancer and HIV therapy. They may also provide some benefit in the treatment of hyperlipidemia, hypertension, and hepatitis.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Anti-HIV Agents; Antibiotics, Antineoplastic; beta-Glucans; Body Weight; Drug Administration Schedule; Glucans; HIV Infections; Humans; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Liver Diseases; Neoplasms; Polyporaceae

Immune enhancement through the use of natural products is a potentially valuable therapeutic modality in HIV-infected people, especially those who are not good candidates for aggressive ARV therapy. One such immune enhancement, a medicinal mushroom product from the United States, is Immune Assist 24/7. In this study the effect of Immune Assist 24/7, which is a naturally derived immune-modulating and antiviral agent, on CD4+ T-lymphocyte counts was evaluated in 8 HIV-infected patients at the Sunyani Regional Hospital (Ghana). The subjects were administered three tablets of 800 mg Immune Assist 24/7 once daily (2.4 g/day) and peripheral blood samples were drawn at baseline, day 30, and day 60, and the CD4+ count measured. The study revealed that Immune Assist 24/7, used as a sole therapeutic agent without additional ARV drugs, significantly increased CD4+ T-lymphocyte populations in all of the patients. In one patient, the CD4+ T-lymphocyte count went from 4 at the baseline, to 170 cells in 60 days, representing an increase of more than 4000%. In another patient, the CD4+ count went from 88 to 470 cells within the same period. Even in the patients with the highest CD4+ counts of around 800, there was a significant elevation in the CD4+ count noted. This study did not deal with the effect of Immune Assist 24/7 on other immune parameters such as CD3+ T-lymphocyte count, natural killer cells count, or viral load among HIV-infected patients. These initial results are promising, and indicate the potential value of further evaluating the effects of Immune Assist 24/7 on other immune parameters and viral load among HIV patients, administered either as a sole therapeutic agent, as an adjuvant with standard ARV therapy, or in comparison with standard ARV therapy alone.

Topics: Adult; Agaricales; Anti-HIV Agents; beta-Glucans; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Female; HIV Infections; HIV-1; Humans; Immunologic Factors; Male; Middle Aged

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which inhibits the attachment of HIV to T-cells, and also has intracellular anti-HIV activity. In Phase I clinical trials, CRDS was found in 4 hr i.v. infusions, to be well tolerated up to 200 mg/70 kg and unexpectedly to produce marked, dose-related increases in CD4 lymphocytes in HIV-infected patients. Prolongation of bleeding time is expected to be the dose limiting toxicity, but no episodes of bleeding were seen. In one of the studies in this report, CRDS was administered i.v. daily for 7 days to HIV patients at doses of 40, 100, 140 and 180 mg/70 kg/day. At the higher doses, marked increases in CD4 and CD8 lymphocytes were observed. These increases mainly returned to baseline after 24 hr. To further delineate the pharmacokinetics of these changes in CD4 and CD8 lymphocytes, another Phase I study was done in which CRDS was infused i.v. over a 30 min period in HIV patients at single doses of 25, 50, 75, 100, 125, 150, 175 and 200 mg/70 kg/day. The drug was well tolerated in all cases and marked increases in CD4 lymphocytes were again seen at the higher doses, in some cases amounting to increases of 500 cells/mm3 after a single dose. The half-life of CRDS in man was found to be about two hours, as measured by activated partial thromboplastin time (APTT) and by plasma assays.

Topics: Antiviral Agents; beta-Glucans; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chromatography, Gel; Glucans; HIV Infections; Humans; Lymphocyte Count; Partial Thromboplastin Time

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which has anti-HIV activity in vitro, and inhibits attachment of the virus to T-cells. After two weeks of exposure of virus and cells to CRDS, there is complete inhibition of virus replication. CRDS is also active against cytomegalovirus. The favorable toxicological profile of CRDS in animals suggested clinical trials. In this study, doses of 0.014, 0.14, 0.42, 1.42, 2.84 and 4.26 mg/Kg (hereinafter referred to as 1, 10, 30, 100, 200 and 300 mg/body, respectively, for convenience) were administered to three HIV-positive patients at each dose level for four hours intravenously. Activated partial thromboplastin times (APTT) were measured hourly. Unexpectedly, single doses of CRDS produced marked, dose-related, increases in CD4 lymphocytes in HIV-infected patients. There were no clinical side effects seen at any dose tested. All laboratory parameters were normal except for prolongation of APTT in the 200 and 300 mg dose group. Two patients in the 300 mg dose group had a doubling of the APTT during the four hour infusion, which was the termination point of the trial according to the protocol. The half-life of CRDS was estimated to be 2 to 3 hours from the APTT data and from the blood level assays (not shown). CRDS was well tolerated in the study with the APTT levels being a convenient monitoring basis for dosing. Marked increases in CD4 levels were seen at higher doses, which, if confirmed and extended, may have therapeutic implications. CRDS is considered safe for multiple dosing with monitoring of APTT.

Topics: Adult; Antiviral Agents; beta-Glucans; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Glucans; HIV Infections; Humans; Male; Middle Aged; Partial Thromboplastin Time

The current study evaluated the diagnostic performance of serum (1,3)-beta-D Glucan (BDG) in differentiating PJP from P. jirovecii-colonization in HIV-uninfected patients with P. jirovecii PCR-positive results.. This was a single-center retrospective study between 2019 and 2021. The diagnosis of PJP was based on the following criteria: detection of P. jirovecii in sputum or BAL specimen by qPCR or microscopy; Meet at least two of the three criteria: (1) have respiratory symptoms of cough and/or dyspnea, hypoxia; (2) typical radiological picture findings; (3) receiving a complete PJP treatment. After exclusion, the participants were divided into derivation and validation cohorts. The derivation cohort defined the cut-off value of serum BDG. Then, it was verified using the validation cohort.. Two hundred and thirteen HIV-uninfected patients were enrolled, with 159 PJP and 54 P. jirovecii-colonized patients. BDG had outstanding specificity, LR, and PPV for PJP in both the derivation (90.00%, 8.900, and 96.43%) and the validation (91.67%, 9.176, and 96.30%) cohorts at ≥ 117.7 pg/mL. However, it had lower sensitivity and NPV in the derivation cohort (89.01% and 72.97%), which was even lower in the validation cohort (76.47% and 57.89%). Of note, BDG ≥ 117.7 pg/mL has insufficient diagnostic efficacy for PJP in patients with lung cancer, interstitial lung disease (ILD) and nephrotic syndrome. And although lymphocytes, B cells, and CD4. Serum BDG ≥ 117.7 pg/mL could effectively distinguish P. jirovecii-colonization from infection in qPCR-positive HIV-uninfected patients with infectious diseases, solid tumors (excluding lung cancer), autoimmune or inflammatory disorders, and hematological malignancies. Of note, for patients with lung cancer, ILD, and nephrotic diseases, PJP should be cautiously excluded at BDG < 117.7 pg/mL.

Topics: beta-Glucans; Glucans; HIV Infections; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies

(1-3)-b-D-glucan (BDG) is a fungal cell wall component and, in the absence of invasive fungal infection, a novel biomarker for microbial translocation of endogenous fungal products from the gastrointestinal tract into systemic circulation. However, its value as a marker of fungal translocation is limited by a concern that plant BDG-rich food influences blood BDG levels.. We conducted a pilot clinical trial to evaluate the impact of a standardised oral BDG challenge on blood BDG levels in participants with and without elevated microbial translocation. We enrolled 14 participants including 8 with HIV infection, 2 with advanced liver cirrhosis, and 4 healthy controls. After obtaining a baseline blood sample, participants received a standardised milkshake containing high levels of BDG followed by serial blood samples up to 8 hours after intake.. The standardised oral BDG challenge approach did not change the blood BDG levels over time in all participants. We found consistently elevated blood BDG levels in one participant with advanced liver cirrhosis and a single person with HIV with a low CD4 count of 201 cells/mm. Our findings indicate that BDG blood levels were not influenced by plant origin BDG-rich nutrition in PWH, people with advanced liver cirrhosis, or healthy controls. Future studies are needed to analyse gut mycobiota populations in individuals with elevated blood BDG levels.

Topics: Adult; beta-Glucans; Biomarkers; Female; Glucans; HIV Infections; Humans; Invasive Fungal Infections; Liver Cirrhosis; Male; Middle Aged; Pilot Projects; Young Adult

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS-related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T cells upon bacterial, fungal, and viral stimulation. PLHIV exhibited an exacerbated proinflammatory profile in monocyte-derived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS, and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of high-sensitivity C-reactive protein and soluble CD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after more than 1 year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte-trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibited a sustained proinflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.

Topics: Adult; Anti-HIV Agents; beta-Glucans; Case-Control Studies; Chronic Disease; Cytokines; Female; Gene Expression; HIV Infections; Humans; Immunity, Innate; Inflammation; Interleukin-1beta; Lipopolysaccharides; Male; Middle Aged; Monocytes; Neutrophils

From clinical case records, we abstracted demographic and clinical information and categorised patients as having confirmed or probable PCP, or an alternative diagnosis. We calculated sensitivity, specificity and positive predictive value (PPV) of serum BDG concentrations >400 pg/mL and negative predictive value (NPV) of BDG <80 pg/mL.. 76 patients were included; 29 had laboratory-confirmed PCP, 17 had probable PCP and 30 had an alternative diagnosis. Serum BDG >400 pg/mL had a sensitivity of 83%, specificity of 97% and PPV 97% for diagnosis of PCP; BDG <80 pg/mL had 100% NPV for exclusion of PCP.. In PWH with suspected PCP, BDG <80 pg/mL excludes a diagnosis of PCP, whereas BDG concentrations >400 pg/mL effectively confirm the diagnosis. Values 80-400 pg/mL should prompt additional diagnostic tests.

Topics: Adult; beta-Glucans; HIV Infections; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity

Regenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH.. Plasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)-uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers.. Cross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH.. Plasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.

Topics: Adult; Anti-HIV Agents; Bacterial Translocation; beta-Glucans; Biomarkers; CD4-CD8 Ratio; Cross-Sectional Studies; Disease Progression; Fatty Acid-Binding Proteins; Female; HIV Infections; HIV-1; Humans; Interleukin-22; Interleukin-6; Interleukin-8; Interleukins; Intestinal Mucosa; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Middle Aged; Pancreatitis-Associated Proteins; Tumor Necrosis Factor-alpha; Viral Load

Topics: beta-Glucans; Glucans; HIV Infections; Humans

Fibrosing interstitial lung disease is the poor prognostic non-infectious lung disease by unknown etiology. Here, we present one case developing interstitial pneumonia with fibrosis after treatment of pneumocystis pneumonia (PCP) in newly diagnosed HIV-1 infected case.. A previously healthy 63-year old male was referred to our institute because of protracted dyspnea on effort in 2 weeks after pneumocystis pneumonia treatment. At referral, arterial blood oxygen pressure was within normal range (93.5 mmHg) at rest, but decreased rapidly 30 s after a slow walk (44.5 mmHg). Respiratory function tests showed severe restrictive ventilator impairment (vital capacity = 36.5%; forced expiratory volume in 1 s = 107.4%). Chest computed tomography showed severe fibrotic changes at bilateral basal parts and diffuse fibrotic changes in which PCP lesions were seen initially in previous images although β-D glucan was not elevated and P. jirovecii was not detected in saliva at referral. Other etiologies of fibrotic IP including infectious and/or autoimmune diseases were excluded by serology. Fibrotic lesion did not expand thereafter although it had not responded to the high-dose corticosteroid therapy.. We report the first case of fibrosing interstitial lung disease triggered by HIV-related PCP.

Topics: AIDS-Related Opportunistic Infections; beta-Glucans; Forced Expiratory Volume; HIV Infections; Humans; Immunocompromised Host; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

Despite antiretroviral therapy (ART), people living with HIV (PLWH) have higher rates of non-AIDS disorders, such as neurocognitive (NC) impairment (NCI) than the general population. (1-3)-β-D-Glucan (BDG) is a fungal cell wall component which serves as a biomarker for gut barrier integrity failure and microbial and fungal translocation. The primary objective of this study was to determine whether higher plasma and cerebrospinal fluid (CSF) levels of BDG and suPAR were associated with NCI in PLWH. Paired blood and CSF samples were collected cross-sectionally from 61 male adult PLWH on ART (95% virally suppressed) who underwent a detailed NC assessment as part of the prospective CHARTER study between 2005 and 2015. BDG and soluble urokinase plasminogen activator receptor (suPAR) were measured in frozen blood and CSF samples while soluble CD14 (sCD14), intestinal fatty acid binding protein (IFABP), and CD4/CD8 ratio were measured in blood only. Spearman's rho correlation analysis assessed associations between BDG, other biomarkers, and NC performance. Median BDG levels were 18 pg/mL in plasma (range 2-60 pg/mL) and 20 pg/mL in CSF (range 0-830 pg/mL). Higher levels of plasma BDG were associated with worse NC performance (Spearman's rho = - 0.32; p = 0.013) and with the presence of NCI (p = 0.027). A plasma BDG cutoff of > 30 pg/mL was 30% sensitive and 100% specific for NCI. After adjusting for age, higher plasma suPAR levels were also associated with worse NC performance (p < 0.01). No significant associations were observed between the remaining biomarkers and the NC variables. Plasma levels of BDG and age-adjusted suPAR may be new biomarkers for the detection of NCI in PLWH on suppressive ART.

Topics: Adult; Anti-Retroviral Agents; beta-Glucans; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Female; HIV Infections; Humans; Male; Middle Aged; Receptors, Urokinase Plasminogen Activator

Natural killer (NK) cells use the activating receptor NKp30 as a microbial pattern-recognition receptor to recognize, activate cytolytic pathways, and directly kill the fungi Cryptococcus neoformans and Candida albicans. However, the fungal pathogen-associated molecular pattern (PAMP) that triggers NKp30-mediated killing remains to be identified. Here we show that β-1,3-glucan, a component of the fungal cell wall, binds to NKp30. We further demonstrate that β-1,3-glucan stimulates granule convergence and polarization, as shown by live cell imaging. Through Src Family Kinase signaling, β-1,3-glucan increases expression and clustering of NKp30 at the microbial and NK cell synapse to induce perforin release for fungal cytotoxicity. Rather than blocking the interaction between fungi and NK cells, soluble β-1,3-glucan enhances fungal killing and restores defective cryptococcal killing by NK cells from HIV-positive individuals, implicating β-1,3-glucan to be both an activating ligand and a soluble PAMP that shapes NK cell host immunity.

Topics: beta-Glucans; Candida albicans; Cell Line; Cell Polarity; Cryptococcus neoformans; Cytoplasmic Granules; Cytotoxicity, Immunologic; HIV Infections; Host-Pathogen Interactions; Humans; Immunological Synapses; Killer Cells, Natural; Ligands; Microscopy, Atomic Force; Natural Cytotoxicity Triggering Receptor 3; Pathogen-Associated Molecular Pattern Molecules; Perforin; Recombinant Proteins; Solubility

Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-β-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals.

Topics: Adult; Aged; Anti-HIV Agents; Bacterial Translocation; beta-Glucans; Biomarkers; CD4 Lymphocyte Count; Cognition Disorders; Cross-Sectional Studies; Female; HIV; HIV Infections; Humans; Interleukin-8; Lipopolysaccharide Receptors; Male; Middle Aged; Neuropsychological Tests; Retrospective Studies; RNA, Viral; Severity of Illness Index

Naturally occurring galactomannans were sulfated to give sulfated galactomannans with degrees of substitution of 0.7-1.4 per sugar unit and molecular weights of M¯n=0.6×10(4)-2.4×10(4). Sulfated galactomannans were found to have specific biological activities in vitro such as anticoagulant, anti-HIV and anti-Dengue virus activities. The biological activities were compared with those of standard dextran and curdlan sulfates, which are polysaccharides with potent antiviral activity and low cytotoxicity. It was found that sulfated galactomannans had moderate to high anticoagulant activity, 13.4-36.6unit/mg, compared to that of dextran and curdlan sulfates, 22.7 and 10.0unit/mg, and high anti-HIV and anti-Dengue virus activities, 0.04-0.8μg/mL and 0.2-1.1μg/mL, compared to those curdlan sulfates, 0.1μg/mL, respectively. The cytotoxicity on MT-4 and LCC-MK2 cells was low. Surface plasmon resonance (SPR) of sulfated galactomannans revealed strong interaction with poly-l-lysine as a model compound of virus proteins, and suggested that the specific biological activities might originate in the electrostatic interaction of negatively charged sulfate groups of sulfated galactomannans and positively charged amino groups of surface proteins of viruses. These results suggest that sulfated galactomannans effectively prevented the infection of cells by viruses and the degree of substitution and molecular weights played important roles in the biological activities.

Topics: Anticoagulants; Antiviral Agents; beta-Glucans; Dengue; Dengue Virus; Galactose; HIV; HIV Infections; Humans; Mannans; Polylysine; Sulfates

Pneumocystis pneumonia (PcP) is a major HIV-related illness caused by Pneumocystis jirovecii. Definitive diagnosis of PcP requires microscopic detection of P. jirovecii in pulmonary specimens. The objective of this study was to evaluate the usefulness of two serum markers in the diagnosis of PcP. Serum levels of (1-3)-beta-d-glucan (BG) and lactate dehydrogenase (LDH) were investigated in 100 HIV-positive adult patients and 50 healthy blood donors. PcP cases were confirmed using indirect immunofluorescence with monoclonal anti-Pneumocystis antibodies and nested-PCR to amplify the large subunit mitochondrial rRNA gene of P. jirovecii in pulmonary specimens. BG and LDH levels in serum were measured using quantitative microplate-based assays. BG and LDH positive sera were statistically associated with PcP cases (P ≤ 0.001). Sensitivity, specificity, positive/negative predictive values (PPV/NPV), and positive/negative likelihood ratios (PLR/NLR) were 91.3 %, 61.3 %, 85.1 %, 79.2 %, 2.359, and 0.142, respectively, for the BG kit assay, and 91.3 %, 35.5 %, 75.9 %, 64.7 %, 1.415 and 0.245, respectively, for the LDH test. Serologic markers levels combined with the clinical diagnostic criteria for PcP were evaluated for their usefulness in diagnosis of PcP. The most promising cutoff levels for diagnosis of PcP were determined to be 400 pg/ml of BG and 350 U/l of LDH, which combined with clinical data presented 92.8 % sensitivity, 83.9 % specificity, 92.8 % PPV, 83.9 % NPV, 5.764 PLR and 0.086 NLR (P < 0.001). This study confirmed that BG is a reliable indicator for detecting P. jirovecii infection. The combination between BG/LDH levels and clinical data is a promising alternative approach for PcP diagnosis.

Topics: Adult; Aged; beta-Glucans; Biomarkers; Female; HIV Infections; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity; Serum; Young Adult

Topics: beta-Glucans; Diagnosis, Differential; HIV Infections; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity

Translocation of gastrointestinal bacteria in HIV-infected individuals is associated with systemic inflammation, HIV progression, mortality, and comorbidities. HIV-infected individuals are also susceptible to fungal infection and colonization, but whether fungal translocation occurs and influences HIV progression or comorbidities is unknown.. Serum (1→3)-β-D-glucan (BG) was measured by a Limulus Amebocyte Lysate assay (Fungitell) in 132 HIV-infected outpatients. Selected plasma cytokines and markers of peripheral T-cell activation were measured. Pulmonary function testing and Doppler echocardiography were performed. Relationship of high (≥40 pg/mL) and low (<40 pg/mL) levels of BG with HIV-associated variables, inflammation markers, and pulmonary function and pulmonary hypertension measures were determined.. Forty-eight percent of patients had detectable BG, and 16.7% had high levels. Individuals with high BG were more likely to have CD4 counts less than 200 cells/μL (31.8% vs. 8.4%, P = 0.002), had higher log10 HIV viral levels (2.85 vs. 2.13 log copies/mL, P = 0.004), and were less likely to use antiretroviral therapy (68.2% vs. 90.0%, P = 0.006). Plasma IL-8 (P = 0.033), TNF-α (P = 0.029), and CD8CD38 (P = 0.046) and CD8HLA-DR (P = 0.029) were also increased with high levels. Abnormalities in diffusing capacity (P = 0.041) and in pulmonary artery pressures (P = 0.006 for pulmonary artery systolic pressure and 0.013 for tricuspid regurgitant velocity) were more common in those with high BG.. We found evidence of peripheral fungal cell wall polysaccharides in an HIV-infected cohort. We also demonstrated an association between high serum BG, HIV-associated immunosuppression, inflammation, and cardiopulmonary comorbidity. These results implicate a new class of pathogen in HIV-associated microbial translocation and suggest a role in HIV progression and comorbidities.

Topics: Adult; beta-Glucans; Cytokines; Echocardiography; Female; HIV Infections; Humans; Hypertension, Pulmonary; Immune Tolerance; Inflammation; Limulus Test; Male; Middle Aged; Mycoses; Outpatients; Proteoglycans; Respiratory Function Tests; Serum; T-Lymphocytes

The number of patients with non-HIV Pneumocystis pneumonia (PCP) is increasing with widespread immunosuppressive treatment. We investigated the clinical characteristics of non-HIV PCP and its association with microbiological genotypes.. Between January 2005 and March 2010, all patients in 2 university hospitals who had been diagnosed with PCP by PCR were enrolled in this study. Retrospective chart review of patients, microbiological genotypes, and association with 30-day mortality were examined.. Of the 82 adult patients investigated, 50 patients (61%) had inflammatory diseases, 17 (21%) had solid malignancies, 12 (15%) had hematological malignancies, and 6 (7%) had received transplantations. All patients received immunosuppressive agents or antitumor chemotherapeutic drugs. Plasma (1→3) β-D-glucan levels were elevated in 80% of patients, and were significantly reduced after treatment in both survivors and non-survivors. However, β-D-glucan increased in 18% of survivors and was normal in only 33% after treatment. Concomitant invasive pulmonary aspergillosis was detected in 5 patients. Fifty-six respiratory samples were stored for genotyping. A dihydropteroate synthase mutation associated with trimethoprim-sulfamethoxazole resistance was found in only 1 of the 53 patients. The most prevalent genotype of mitochondrial large-subunit rRNA was genotype 1, followed by genotype 4. The most prevalent genotype of internal transcribed spacers of the nuclear rRNA operon was Eb, followed by Eg and Bi. Thirty-day mortality was 24%, in which logistic regression analysis revealed association with serum albumin and mechanical ventilation, but no association with genotypes.. In non-HIV PCP, poorer general and respiratory conditions at diagnosis were independent predictors of mortality. β-D-glucan may not be useful for monitoring the response to treatment, and genotypes were not associated with mortality.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; DNA, Bacterial; DNA, Mitochondrial; Female; Genotype; HIV Infections; Humans; Japan; Male; Middle Aged; Opportunistic Infections; Pneumocystis carinii; Pneumonia, Pneumocystis; Prognosis; Retrospective Studies; Young Adult

Topics: beta-Glucans; Diagnostic Tests, Routine; HIV Infections; Humans; Plasma; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Serologic Tests

(See the editorial commentary by Morris and Masur, on pages 203-204.). Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 → 3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs).. The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥ 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites.. A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP.. Blood (1 → 3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.

Topics: Adult; beta-Glucans; Diagnostic Tests, Routine; Female; HIV Infections; Humans; Male; Plasma; Pneumocystis carinii; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

Topics: beta-Glucans; Diagnostic Tests, Routine; Female; HIV Infections; Humans; Male; Pneumocystis carinii; Pneumonia, Pneumocystis

Topics: beta-Glucans; HIV Infections; Humans; Pneumonia, Pneumocystis; Proteoglycans; Serum

Histoplasma capsulatum (Hc) is a facultative, intracellular parasite of worldwide significance. Infection with Hc produces a broad spectrum of diseases and may progress to a life-threatening systemic disease, particularly in individuals with HIV infection. Resolution of histoplasmosis is associated with the activation of cell-mediated immunity, and leukotriene B(4) plays an important role in this event. Lipid bodies (LBs) are increasingly being recognized as multifunctional organelles with roles in inflammation and infection. In this study, we investigated LB formation in histoplasmosis and its putative function in innate immunity. LB formation in leukocytes harvested from Hc-infected C57BL/6 mice peaks on day 2 postinfection and correlates with enhanced generation of lipid mediators, including leukotriene B(4) and PGE(2). Pretreatment of leukocytes with platelet-activating factor and BLT1 receptor antagonists showed that both lipid mediators are involved in cell signaling for LB formation. Alveolar leukocytes cultured with live or dead Hc also presented an increase in LB numbers. The yeast alkali-insoluble fraction 1, which contains mainly beta-glucan isolated from the Hc cell wall, induced a dose- and time-dependent increase in LB numbers, indicating that beta-glucan plays a signaling role in LB formation. In agreement with this hypothesis, beta-glucan-elicited LB formation was inhibited in leukocytes from 5-LO(-/-), CD18(low) and TLR2(-/-) mice, as well as in leukocytes pretreated with anti-Dectin-1 Ab. Interestingly, human monocytes from HIV-1-infected patients failed to produce LBs after beta-glucan stimulation. These results demonstrate that Hc induces LB formation, an event correlated with eicosanoid production, and suggest a role for these lipid-enriched organelles in host defense during fungal infection.

Topics: Adult; Animals; beta-Glucans; CD18 Antigens; Cell Wall; Enzyme-Linked Immunosorbent Assay; Female; Histoplasma; Histoplasmosis; HIV Infections; HIV-1; Humans; Lectins, C-Type; Leukocytes, Mononuclear; Leukotriene B4; Lipids; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nerve Tissue Proteins; Organelles; Toll-Like Receptor 2

High serum (1-->3) beta-D-glucan levels are described in patients with Pneumocystis pneumonia (PCP). We evaluated the diagnostic value of beta-D-glucan in 111 patients with AIDS who had PCP and confirmed its usefulness. However, it does not correlate with disease severity and is not suitable for monitoring response to treatment.

Topics: Adult; beta-Glucans; Biomarkers; Female; HIV Infections; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans

(1-3)-Beta-D-Glucan (BG) reactivity was tested in serum samples from 28 patients with human immunodeficiency virus infection or a hematological malignancy and Pneumocystis jirovecii pneumonia (PCP) and 28 control patients. The sensitivity and specificity of BG detection with the Fungitell assay for PCP were 100 and 96.4%, respectively, using a cutoff value of 100 pg/ml. Serum BG testing looks promising for the noninvasive diagnosis of PCP. Our data suggest that a higher cutoff value for the diagnosis of PCP than for the diagnosis of invasive aspergillosis or candidiasis could be used safely and will improve the specificity of the test.

Topics: Adult; AIDS-Related Opportunistic Infections; beta-Glucans; Female; Hematologic Neoplasms; HIV Infections; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Sensitivity and Specificity; Young Adult

Topics: Adult; Antifungal Agents; beta-Glucans; Bronchoalveolar Lavage Fluid; HIV Infections; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Radiography, Thoracic; Sputum

Topics: Adult; Aged; beta-Glucans; Female; HIV Infections; Humans; Immunocompromised Host; Male; Middle Aged; Pneumocystis carinii; Pneumocystis Infections; Prospective Studies; Proteoglycans; Serum

Topics: Anti-HIV Agents; beta-Glucans; Down-Regulation; Glucans; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Receptors, CCR5

Action mechanisms of a newly synthesized polysaccharide, curdlan sulfate (CRDS), on human immunodeficiency virus type 1 (HIV-1) infection were investigated in vitro using syncytium formation microassay and p24 antigen capture enzyme-linked immunosorbent assay. These assays measured the titer of infectious virions and the amounts of HIV-1 core antigen p24 in soluble, intraviral, and intracellular forms. CRDS treatments were performed for 1 h at 37 degrees C. H9 cells pretreated with 0.1 to 100.0 micrograms/ml of CRDS appreciably inhibited HIV-1 infection. CRDS-treated HIV-1 virions were less able to infect H9 cells than untreated virions. The simultaneous treatment of H9 cells and HIV-1 virions with CRDS induced a significant inhibition of HIV-1 infection, resulting in the temporary disappearance of virions at the highest dose of CRDS. In contrast, CRDS treatment of newly HIV-1-infected H9 cells caused a significant decrease in the titer of infectious HIV-1 and the p24 amounts of all three forms, but no absolute elimination. Taken together, these results indicate that CRDS may block the binding of the HIV-1 envelope to the H9 cell surface, with emphasis on the high affinity of CRDS to the HIV-1 envelope.

Topics: Antiviral Agents; beta-Glucans; CD4-Positive T-Lymphocytes; Cell Line; Enzyme-Linked Immunosorbent Assay; Gene Products, gag; Glucans; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Viral Core Proteins; Virion; Virus Replication