Karin K. Pedersen

Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction.

Objective:Microbial translocation has been suggested to be a driver of immune activation and inflammation. It is hypothesized that microbial translocation may be related to dyslipidemia, insulin resistance, and the risk of coronary heart disease in HIV-infected individuals. Design:Cross-sectional study of 60 HIV-infected patients on combination antiretroviral therapy with viral suppression >2 years and 31 healthy age-matched controls. Methods:Lipopolysaccharide (LPS) was analyzed by limulus amebocyte lysate colorimetric assay. Lipids, including cholesterol, low-density lipoprotein (LDL), and triglycerides, were measured. Glucose metabolism was determined using an oral glucose tolerance test. Body composition was determined using whole-body dual-energy x-ray absorptiometry scans and magnetic resonance imaging. The Framingham risk score was used to assess risk of cardiovascular disease and myocardial infarction. Results:HIV-infected patients had higher level of LPS compared with controls (64 pg/mL vs. 50 pg/mL, P = 0.002). Likewise, HIV-infected patients had higher triglycerides, LDL, and fasting insulin as well as evidence of lower insulin sensitivity compared with controls. Among HIV-infected patients, high LPS was associated with a higher level of triglycerides and LDL and with lower insulin sensitivity. Importantly, among HIV-infected patients, high LPS was associated with a higher Framingham risk score. Conclusions:HIV-infected patients with suppressed viral replication had increased level of microbial translocation as measured by LPS. LPS was associated with cardiometabolic risk factors and increased Framingham risk score. Hence, the gastrointestinal mucosal barrier may be a potential therapeutic target to prevent dyslipidemia and future cardiovascular complications in HIV infection.

Cognitive Functions in Middle Aged Individuals Are Related to Metabolic Disturbances and Aerobic Capacity: A Cross-Sectional Study

Aims Metabolic disturbances may contribute to cognitive dysfunction in patients with type 2 diabetes. We investigated the relation between cognitive impairment and metabolic deteriorations, low physical fitness, low-grade inflammation and abdominal obesity in middle aged individuals. Methods We conducted a cross-sectional study including 40 to 65 year-old patients with type 2 diabetes and limited co morbidity (N = 56), age-matched individuals with impaired glucose tolerance (N = 56) as well as age-matched controls with normal glucose tolerance (N = 72). Specific cognitive functions were assessed with focus on verbal memory, processing speed, executive functions, and a composite overall mean score. Oral glucose tolerance test, VO2max test, systemic inflammation, DXA scanning and abdominal MRI were measured. Results Multiple linear regression analyses adjusting for age, gender and verbal intelligence demonstrated that a low score in processing speed, executive functions and overall cognitive function were related to high fasting C-peptide, as well as low insulin sensitivity, beta-cell function and VO2max. Measurements of blood glucose, obesity and inflammation were not associated with cognitive function. Conclusion Low cognitive scores are seen in middle aged individuals with hyperinsulinemia, low insulin sensitivity, beta-cell function and low aerobic capacity. These findings emphasize the importance of appropriate lifestyle and not only blood glucose control in prevention of cognitive disability.

Persisting inflammation and chronic immune activation but intact cognitive function in HIV-infected patients after long-term treatment with combination antiretroviral therapy.

Objectives:Impaired cognitive function in HIV-infected patients has been suggested. Treatment with combination antiretroviral therapy (cART) restores CD4+ cell counts and suppresses viral replication, but immune activation and inflammation may persist. The aim of the study was to examine if cognitive function in HIV-infected patients was related to immune activation and inflammation. Methods:Sixty-one HIV-infected patients and 31 healthy controls were included. All patients were on treatment with cART, had suppressed viral replication, and had a mean CD4+ cell count of 522 cells/&mgr;L. Cognitive function was assessed using a test battery of neurocognitive tests. Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-&agr; (TNF-&agr;), and &bgr;-2-microglobulin were measured. Immune activation (CD8+HLR-DR+CD38+ cells) was determined using flow cytometry. Multiple linear regression analysis was performed to identify relationship between cognitive scores and markers of inflammation and immune activation. Results:HIV-infected patients had intact cognitive function compared with healthy controls. Higher levels of TNF-&agr;, &bgr;-2-microglobulin, and chronic activated CD8+ cells were found in HIV-infected patients (P = 0.0002, P < 0.0001, and P = 0.021, respectively). Weak negative correlations were found between chronic activated CD8+ cells (&bgr;-coefficient = −0.277, P = 0.044), IL-6 (&bgr;-coefficient = −0.280, P = 0.014), and memory and learning. Conclusions:HIV-infected patients on cART with undetectable viral load had an increased level of inflammation and immune activation. However, intact cognitive function was found, and only weak correlations were found between cognitive function and markers of inflammation and immune activation, indicating that peripheral inflammation and immune activation are not major drivers of cognitive decay in HIV-infected patients.

Increased shelterin mRNA expression in peripheral blood mononuclear cells and skeletal muscle following an ultra-long-distance running event

Located at the end of chromosomes, telomeres are progressively shortened with each replication of DNA during aging. Integral to the regulation of telomere length is a group of proteins making up the shelterin complex, whose tissue-specific function during physiological stress is not well understood. In this study, we examine the mRNA and protein levels of proteins within and associated with the shelterin complex in subjects (n = 8, mean age = 44 yr) who completed a physiological stress of seven marathons in 7 days. Twenty-two to 24 h after the last marathon, subjects had increased mRNA levels of DNA repair enzymes Ku70 and Ku80 (P < 0.05) in both skeletal muscle and peripheral blood mononuclear cells (PBMCs). Additionally, the PBMCs displayed an increment in three shelterin protein mRNA levels (TRF1, TRF2, and Pot-1, P < 0.05) following the event. Seven days of ultrarunning did not result in changes in mean telomere length, telomerase activity, hTert mRNA, or hterc mRNAs found in PBMCs. Higher protein concentrations of TRF2 were found in skeletal muscle vs. PBMCs at rest. Mean telomere length in skeletal muscle did not change and did not contain detectable levels of htert mRNA or telomerase activity. Furthermore, changes in the PBMCs could not be attributed to changes in the proportion of subtypes of CD4(+) or CD8(+) cells. We have provided the first evidence that, in humans, proteins within and associated with the shelterin complex increase at the mRNA level in response to a physiological stress differentially in PBMCs and skeletal muscle.

Normal physical activity obliterates the deleterious effects of a high-caloric intake

A high-caloric intake combined with a sedentary lifestyle is an important player in the development of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine if the level of physical activity has impact on the metabolic effects of a high-caloric (+2,000 kcal/day) intake. Therefore, healthy individuals on a high-caloric intake were randomized to either 10,000 or 1,500 steps/day for 14 days. Step number, total energy expenditure, dietary records, neuropsychological tests, maximal oxygen uptake (Vo2max), whole body dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) scans, continuous glucose monitoring (CGM), and oral glucose tolerance tests (OGTT) with stable isotopes were performed before and after the intervention. Both study groups gained the same amount of body weight. However, the inactive group accumulated significantly more visceral fat compared with the active group. Following the 2-wk period, the inactive group also experienced a poorer glycemic control, increased endogenous glucose production, decreased hepatic insulin extraction, increased baseline plasma levels of total cholesterol and LDL, and a decreased cognitive function with regard to capacity of attention. In conclusion, we find evidence to support that habitual physical activity may prevent pathophysiological symptoms associated with diet-induced obesity.

Circulating levels of HMGB1 are correlated strongly with MD2 in HIV-infection: Possible implication for TLR4-signalling and chronic immune activation

Progressive HIV infection is characterized by profound enterocyte damage, microbial translocation and chronic immune activation. We aimed to test whether High Mobility Group Box protein 1(HMGB1), a marker of cell death, alone, or in combination with LPS, might contribute to HIV-associated immune activation and progression. Altogether, 29 untreated HIV-infected individuals, 25 inflammatory bowel disease (IBD) patients and 30 controls were included. HIV-infected patients had lower plasma LPS levels than IBD patients, but higher levels of soluble CD14 and Myeloid Differentiation (MD) 2, which interacts with TLR4 to initiate LPS-signalling. Furthermore, plasma levels of HMGB1 and MD2 were correlated directly within the HIV-infected cohort (r = 0.89, P < 0.001) and the IBD-cohort (r = 0.85, P < 0.001), implying HMGB1 signalling through the MD2/TLR4-pathway. HMGB1 and LPS, although not inter-correlated, were both moderately (r = 0.4) correlated with CD38 density on CD8+ T cells in HIV progressors. The highest levels of CD38 density and MD2 were found in progressors with plasma levels of both LPS and HMGB1 above the fiftieth percentile. Our results could imply that, in some patients, immune activation is triggered by microbial translocation, in some by cell death and in some by HMGB1 in complex with bacterial products through activation of the MD2/TLR4-pathway.

Lower Self-Reported Quality of Life in HIV-Infected Patients on cART and With Low Comorbidity Compared With Healthy Controls.

Background:Self-reported quality of life (QoL) has previously been found to be impaired in patients living with HIV and associated with viral replication, degree of immunodeficiency, and comorbidity. We aimed at investigating QoL in a group of HIV-infected patients with suppressed viral replication and with low comorbidity, compared with healthy controls. We furthermore aimed to identify factors associated with QoL. Design and Methods:Cross-sectional study of 52 HIV-infected patients and 23 healthy controls matched on age, gender, education, and comorbidity. HIV-infected patients and healthy controls had previously been examined regarding cognitive, physical, metabolic, and immunological parameters. QoL was investigated using the Medical Outcomes Study HIV Health Survey (MOS-HIV). Linear multiple regression models were created to find factors associated with mental health summary score (MHS) and physical health summary score (PHS). Results:HIV-infected patients reported lower QoL compared with controls. In HIV-infected patients, female gender and depression score were associated with lower MHS. In controls, years of education, depression score, and cognitive test performance were associated with lower MHS. In HIV-infected patients, years of education, depression score, and body mass index were associated with lower PHS, whereas in controls, years of education and fitness level were associated with PHS. Conclusions:Even well-treated HIV-infected patients with low level of comorbidity reported lower QoL compared with healthy controls. Especially, depression score and body mass index were associated with QoL in HIV-infected patients.

Monocyte activation, but not microbial translocation, is independently associated with markers of endovascular dysfunction in HIV-infected patients receiving cART.

Background:Microbial translocation has been suggested as a driver of cardiovascular disease in HIV infection. We hypothesized that microbial translocation and the resulting monocyte activation would be associated with markers of endovascular dysfunction. Methods:In 60 HIV-infected patients on combination antiretroviral therapy, plasma levels of lipopolysaccharide, soluble CD14 (sCD14), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were measured. Results:ADMA and SDMA were associated with sCD14 but not lipopolysaccharide. There was a significant increase in ADMA and SDMA through tertiles of sCD14, and both markers were associated with sCD14 in multivariate linear regression analyses. Conclusions:Monocyte activation as measured by sCD14 is associated with endovascular dysfunction in HIV infection.

MicroRNA-210, microRNA-331 and microRNA-7 are differentially regulated in treated HIV-1-infected individuals, and are associated with markers of systemic inflammation.

Objective: Inflammation may contribute to an increased risk of cardiovascular disease (CVD) in HIV-1 infection. MicroRNAs (miRNAs) are involved in the regulation of inflammation. In treated HIV-1–infected individuals, we aimed to identify differentially expressed miRNAs with known roles in inflammation and CVD risk and to investigate associations between these and systemic inflammation. Methods: In a screening cohort including 14 HIV-1–infected individuals and 9 uninfected controls, microarray profiling was performed using peripheral blood mononuclear cells (PBMCs). Differentially regulated miRNAs previously related to inflammation and CVD were validated using real-time quantitative reverse-transcription polymerase chain reaction in 26 HIV-1–infected individuals and 20 uninfected controls. Validated miRNAs were measured in PBMCs, CD4+ and CD8+ T cells. Interleukin-6, tumor necrosis factor-alpha, high-sensitivity C-reactive protein, lipopolysaccharide (LPS), cytomegalovirus immunoglobulin G, lipids, and fasting glucose were measured, and associations with validated miRNAs were assessed with multiple linear regression analysis. Results: Upregulation of miR-210, miR-7, and miR-331 was found in PBMCs from HIV-1–infected individuals when compared with those from uninfected controls (P < 0.005). In contrast, miR-210 and miR-331 were downregulated in CD8+ T cells. In multivariate analysis, miR-210 in CD8+ T cells was negatively associated with LPS (P = 0.023) and triglycerides (P = 0.003) but positively associated with tumor necrosis factor-alpha (P = 0.004). MiR-7 in PBMC was positively associated with interleukin-6 (P = 0.025) and fasting glucose (P = 0.005), whereas miR-331 was negatively associated with LPS (P = 0.006). In PBMCs from HIV-1–infected individuals with low cytomegalovirus immunoglobulin G, miR-7, miR-29a, miR-221, and miR-222 were downregulated. Conclusion: In 2 independent cohorts, miR-210, miR-7, and miR-331 were differentially regulated in treated HIV-1–infected individuals and associated with markers of systemic inflammation.

Marker of Endothelial Dysfunction Asymmetric Dimethylarginine Is Elevated in HIV Infection but Not Associated With Subclinical Atherosclerosis.

Background:Cardiovascular disease contributes to excess morbidity and mortality in HIV infection, and endothelial dysfunction may contribute to this pattern. We aimed to determine the endothelial function in treated and untreated HIV-infected individuals and investigate potential associations with viral replication, immune activation, coagulation, platelet function, and subclinical atherosclerosis. Methods:Asymmetric dimethylarginine (ADMA, marker of endothelial dysfunction) and soluble CD14 (sCD14, marker of monocyte activation) were measured in plasma from two previously established cross-sectional cohorts: cohort A including 50 untreated and 50 antiretroviral therapy (ART)–treated HIV-infected individuals with previously assessed coagulation and platelet function and cohort B including 105 HIV-infected individuals on ART and 105 uninfected controls with previously assessed coronary artery calcium score, myocardial perfusion defects, and carotid intima–media thickness. Results:Concentrations of ADMA were higher in HIV-infected individuals compared with uninfected controls, and higher ADMA was found in ART-treated compared with untreated HIV-infected individuals. ADMA was associated with viral load, sCD14, D-dimer, and low CD4+ T-cell count in untreated HIV infection. Only viral load remained significant in multivariate analyses. In ART-treated HIV-infected individuals, ADMA was not associated with coronary artery calcium score, myocardial perfusion defects, or intima–media thickness. Conclusions:Evidence of endothelial dysfunction was found in HIV infection and in untreated compared with treated HIV infection. In untreated HIV infection, the main driver of endothelial dysfunction was viral replication. Importantly, in treated HIV infection, ADMA was not associated with subclinical atherosclerosis. Thus, our data question the potential of ADMA as a useful biomarker of early atherosclerosis in treated HIV infection.