436 research outputs found
The role of microbial translocation and gut microbiota in HIV-1 infection
No full textHIV-1 infection is characterized by persistent systemic inflammation and immune activation, even in patients receiving effective antiretroviral therapy (ART). Translocation of microbial compounds from a leaky gut to systemic circulation, so called microbial translocation (MT), is a major driver of the immune activation. Additionally, gut microbiota dysbiosis in HIV-1 infected patients further facilitate and fuel MT. The objectives of this thesis were to study: * how different ART regimens and usage of antibiotics affect markers of MT (I, II), * the alternations of gut microbiota during HIV-1 infection and the effect of ART (III,IV).In a clinical randomized trial, HIV-1 infected subjects started ART based on efavirenz (n=37) or ritonavir-boosted lopinavir (n=34). Levels of MT markers and of enterocyte death were elevated at baseline (BL), and MT markers declined until follow up after 72 weeks, but the reduction of anti-flagellin IgG antibodies was significant only in lopinavir treated patients. Levels of Intestinal Fatty Acid Binding Protein (I-FABP) remained unchanged at 72 weeks, but were temporarily increased after one month in efavirenz treated patients. 29 subjects with concomitant use of antibiotics had superior reduction of soluble CD14 (sCD14) levels. These data show that choice of ART and antibiotics usage could affect the kinetics of some MT markers.To further explore the impact of antibiotics usage on MT, we performed a longitudinal study on HIV-1 patients initiating ART without (n=13) or with (n=13) co-trimoxazole (TMP-SMX) as prophylaxis against Pneumocystis jirovecii. Following ART, levels of LPS-binding protein (LBP) were reduced only in the TMP-SMX group, whilst levels of sCD14 declined in both groups after one year. The LBP decrease remained significant in a multivariate analysis model adjusting for co-variates including BL CD4+ T-cell count. This study confirmed that concomitant use of antibiotics and ART in severely immune deteriorated individuals may beneficially influence the kinetics of MT markers.In the third study, the composition of gut microbiota was determined by 16S rRNA sequencing in 28 HIV-1 progressors, 3 Elite controllers (EC) and 9 uninfected controls at BL, and additionally after ten months of ART in 16 subjects. Gut microbiome α-diversity was reduced in HIV-1 infected individuals as compared to controls, and further declined after introduction of ART. At BL, α-diversity was positively correlated with CD4+ T-cell counts, but in contrary several markers of MT/immune activation were inversely correlated. Microbiome of EC had the lowest interindividual variation (ß-diversity), clustering together in PCoA analysis. The bacterial composition at genus level was altered in HIV-1 progressors with higher abundance of Lactobacillus, and depletion of Lachnobacterium, Faecalibacterium and Hemophilus. Thus, this study showed that the alternations of gut microbiota during HIV-1 infection are associated with the level of immune dysfunction, and that almost one year of ART does not restore the shifts in the gut microbiome.In the last work, we studied the gut microbiome of 16 EC in relation to 32 matched ART naive HIV-1 positive individuals and 16 uninfected controls. The number of observed genera and richness indices Chao-1 and ACE were significantly higher in EC as compared to naive patients. The gut microbiota in EC was enriched in genera Succinivibrio, Sutterella, Rhizobium, Delftia, Anaerofilum and Oscillospira, whilst Blautia and Anaerostipes were reduced. Determination of inferred bacterial functionality by PICRUSt analysis revealed that carbohydrate metabolism related genes were depleted in EC. In contrary, pathways related to fatty acid metabolism, PPAR-signaling and lipid biosynthesis proteins were more abundant in EC vs naive. The kynurenine pathway of tryptophan metabolism was altered only during progressive HIV-1 infection, and kynurenine tryptophan (K/T) ratio was inversely associated with gut microbiota richness. This study shows that EC have richer gut microbiota than untreated HIV-1 patients with progressive infection, with a unique bacterial composition and a distinct metabolic profile which may be involved in the control of HIV-1.In summary, data from the studies in my thesis reveal that MT in HIV-1 infection is reduced by ART but also that the choice of ART influences this decline. Additionally, the antibiotics usage may affect the levels of MT. The complexity, composition and functionality of gut microbiota are disturbed in HIV-1 infected individuals with progressive disease, whilst EC have a unique gut microbiota profile that eventually contributes to their control of HIV-1.List of scientific papersI. Vesterbacka Jan, Nowak Piotr, Barqasho Babilonia, Abdurahman Samir, Nyström Jessica, Nilsson Staffan, Funaoka Hiroyuki, Kanda Tatsuo, Andersson Lars-Magnus, Gisslèn Magnus, Sönnerborg Anders. Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy. PLoS One. 2013;8(1):e55038. https://doi.org/10.1371/journal.pone.0055038 II. Vesterbacka Jan, Barqasho Babilonia, Häggblom Amanda, Nowak Piotr. Effects of Co-Trimoxazole on Microbial Translocation in HIV-1-Infected Patients Initiating Antiretroviral Therapy. AIDS Res Hum Retroviruses. 2015 Aug;31(8):830-6. https://doi.org/10.1089/AID.2014.0366 III. Nowak Piotr, Troseid Marius, Avershina Ekatarina, Barqasho Babilonia, Neogi Ujjwal, Holm Kristian, Hov Johannes R, Noyan Kajsa, Vesterbacka Jan, Svärd Jenny, Rudi Knut, Sönnerborg Anders. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS. 2015 Nov;29(18):2409-18. https://doi.org/10.1097/QAD.0000000000000869 IV. Vesterbacka Jan, Rivera Javier, Noyan Kajsa, Parera Mariona, Neogi Ujjwal, Calle Malu, Paredes Roger, Sönnerborg Anders, Noguera-Julian Marc, Nowak Piotr. Richer gut microbiota with distinct metabolic profile in HIV infected Elite Controllers. Sci Rep. 2017 Jul 24;7(1):6269. https://doi.org/10.1038/s41598-017-06675-1 </p
Immunometabolic reprogramming during suppressive HIV-1 infection
No full textSince the implementation of antiretroviral therapy (ART), infection with human immunodeficiency virus type-1 (HIV-1) has been transformed into a chronic lifelong condition. The main obstacle for a HIV-1 cure is the persistence of latently infected cells in viral reservoirs. The viral endurance can instigate detrimental changes on the function and activity of immune cells, creating a chronic inflammatory environment in people living with HIV-1 (PLWH) on successful long-term suppressive antiretroviral therapy (PLWHART). The continuous activation of immune cells may lead to an earlier onset of age-related diseases. Immunometabolism is an emerging field that studies how metabolic reprogramming has an impact on the activation, differentiation, and function of immune cells. Given that these underlying processes are likely to contribute to chronic inflammation in PLWH, the overall aim of this thesis was to evaluate how immunometabolism is reprogrammed during “controlled” HIV-1 infection, either by ART in PLWHART or in PLWH with natural control of infection, elite controllers (PLWHEC).In paper I, we integrated proteomic and transcriptomic data to investigate features distinct to the PLWHEC phenotype in a male cohort. We identified dysregulated hypoxia inducible factor (HIF) signalling and altered metabolism as unique characteristics of the male PLWHEC phenotype. As controlled HIV-1 infection still induce changes in the immune system we aimed to compare differences in the immune phenotype between PLWHEC and PLWHART and its relation to HIV-1 persistence in paper II. We identified a unique phenotype of decreased CCR6 expression on CD4+ and CD8+ T cells in PLWHEC compared to PLWHART and healthy controls (HC). Additionally, the CD4+CCR6+ cells exhibited a proteomic profile indicative of increased sensitivity towards cell death mechanisms in PLWHEC compared to PLWHART. A reduced proportion of integrated HIV-1 DNA in the reservoir of PLWHEC was found, although no difference in the amount of intact provirus. Continuing our evaluation of differences between PLWHEC and PLWHART we performed metabolo-transcriptomic analysis to understand and infer changes on a multisystem level in paper III. We detected a system level metabolic aberration mainly revolving around OXPHOS in PLWHART compared to PLWHEC. Using pharmacological modulation, we identified how this dysregulation of OXPHOS possibly affects HIV-1 reservoir dynamics and the immune senescence profile. Furthermore, to understand how HIV-1 chronicity affects long-lasting metabolic flexibility and adaptation we conducted plasma metabolomics to understand alterations during suppressive ART in a Swedish cohort in paper IV. We also aimed to characterize the cell populations that mainly contribute to changes in the metabolic environment. We detected aberrant energy metabolism in PLWHART, mainly revolving around the tricarboxylic acid cycle and amino acid synthesis. Cell-type specific evaluation showed that the main metabolic alterations occurred on monocytic cell populations, and that PLWHART exhibited dysregulated chemokine receptor expression of CCR2, CCR5, and CX3CR1 on myeloid cell lineages. In paper V, we wanted to evaluate if the altered metabolic environment was consistent on a global scale using two cohorts from low and middle-income countries (namely, Cameroon and India) using plasma metabolomics. We detected a dysregulation of amino acid metabolism and a switch towards glutaminolysis during long-term suppressive ART.In summary, the research covered in this thesis illuminates the importance of metabolic reprogramming during HIV-1 persistence in PLWH with controlled infection.List of scientific papersI. Sara Svensson Akusjärvi*, Anoop T Ambikan*, Shuba Krishnan, Soham Gupta, Maike Sperk, Ákos Végvári, Flora Mikaeloff, Katie Healy, Jan Vesterbacka, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi. Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype: A cross-talk between glycolysis and HIF signaling. iScience, 2022 Jan 21; 25(1):103607. *Equal contribution. https://doi.org/10.1016/j.isci.2021.103607 II. Sara Svensson Akusjärvi, Shuba Krishnan, Bianca B. Jütte, Anoop T Ambikan, Soham Gupta, Jimmy Esneider Rodriguez, Ákos Végvári, Maike Sperk, Piotr Nowak, Jan Vesterbacka, J. Peter Svensson, Anders Sönnerborg, and Ujjwal Neogi. Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individual. Communications Biology, 2022 April 13; 5(1):357. https://doi.org/10.1038/s42003-022-03315-x III. Anoop T Ambikan*, Sara Svensson Akusjärvi*, Shuba Krishnan, Maike Sperk, Piotr Nowak, Jan Vesterbacka, Anders Sönnerborg, Rui Benfeitas, and Ujjwal Neogi. Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV-infection. *Equal contribution. [Accepted] https://doi.org/10.26508/lsa.202201405 IV. Sara Svensson Akusjärvi, Shuba Krishnan, Anoop T Ambikan, Flora Mikaeloff, Sivasankaran Munusamy Ponnan, Jan Vesterbacka, Magda Lourda, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi. Monocyte driven systemlevel inflammatory and immunometabolic dysregulation during prolonged successful HIV-1 treatment. [Manuscript]V. Flora Mikaeloff, Sara Svensson Akusjärvi, George Mondinde Ikomey, Shuba Krishnan, Maike Sperk, Soham Gupta, Gustavo Daniel Vega Magdaleno, Alejandra Escós, Emilia Lyonga, Marie Claire Okomo, Claude Tayou Tagne, Hemalatha Babu, Christian L. Lorson, Ákos Végvári, Akhil C. Banerjea, Julianna Kele, Luke Elizabeth Hanna, Kamal Singh, João Pedro de Magalhães, Rui Benfeitas, and Ujjwal Neogi. Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection. Communications Biology, 2022 Jan 11;5(1):27. https://doi.org/10.1038/s42003-021-02985-3 </p
Successful Combination Treatment for Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Infection
No full textSimulating Behavioral Level On-Chip Noise Coupling [Elektronisk resurs]
No full textIn this thesis, noise coupling simulation is introduced into the behavioral level. Methods andmodels for simulating on-chip noise coupling at the behavioral level in a design flow are presentedand verified for accuracy and validity. Today, designs of electronic systems are becoming denserand more and more mixed-signal systems such as System-on-Chip (SoC) are being devised. Thisraises problems when the electronics components start to interfere with each other. Often, digitalcomponents disturb analog components, introducing noise into the system causing degradation ofthe performance or even introducing errors into the functionality of the system.Today, these effects can only be simulated at a very late stage in the design process, causinglarge design iterations and increased costs if the designers are required to return and makealterations, which may have occurred at a very early stage in the process.This is why the focus of this work is centered on extracting noise coupling simulation modelsthat can be used at a very early design stage, such as at the behavioral level and then follow thedesign through the various design stages. To achieve this, SystemC is selected as a platform andimplementation example for the behavioral level models. SystemC supports design refinement,which means that when designs are being refined and are crossing the design levels, the noisecoupling models can also be refined to suit the current design.This new method of thinking in primarily mixed-signal designs is called Behavioral levelNoise Coupling (BeNoC) simulation and shows great promise in enabling a reduction in the costsof design iterations due to component cross-talk and simplifies the work for mixed-signal systemdesigners.I denna avhandling introduceras brussimulering i mikrochip på en beteendenivå. Metoderoch modeller för brussimulering i chip presenteras och verifieras för noggrannhet och funktionalitetpå en beteendenivå i designflödet. I dagsläget blir elektroniska system tätare och tätare på chippenoch fler och fler system görs med både analog och digital elektronik såsom System-on-Chip (SoC).Detta skapar problem när komponenter börjar störa varandra. Oftast är det digitala komponentersom stör de analoga, vilket introducerar brus i systemet som reducerar prestanda eller till och medinför fel i funktionen hos systemet.Idag kan dessa effekter simuleras i ett mycket sent skede i designflödet, betyder att om felupptäcks måste designern kanske gå tillbaka många steg i flödet. Detta kostar mycket tid ochpengar.Därför ligger fokus i detta arbete på att extrahera brussimuleringsmodeller som kananvändas i ett tidigt skede såsom på beteendenivå och sedan följa designen genom senare skeden idesignflödet. För att realisera detta har SystemC valts som en plattform och som ettimplementationsexempel för beteendenivåmodellerna. SystemC har stöd för förfining av designervilket betyder att ett system kan börja beskrivas på en hög nivå för att sedan förfinas för att nå lägrenivåer. Detta gör det möjligt för brusmodellerna att också förfinas i takt med systemdesignen.Detta nya sätt att tänka på i designprocessen av i huvudsak analog/digital-integreradesystem kallas Behavioral level Noise Coupling (BeNoC) simulering och bådar gott för att reducerakostnader för designiterationer på grund av brus mellan komponenter, och gör arbetet enklare föranalog/digital- (mixed-signal) designers.</p
Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium
No full textBACKGROUND: Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. METHODS: The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. RESULTS: 14 703 people were included in this study, of whom 7863 (53·5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1·27, 95% CI 1·17-1·38), raltegravir (1·37, 1·20-1·56), and tenofovir alafenamide (1·38, 1·22-1·35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2·10, 1·91-2·31 for underweight vs healthy weight) and Black ethnicity (1·61, 1·47-1·76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0·97, 0·96-0·98 per 100 cells per μL increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1·21, 95% CI 1·19-1·32) and tenofovir alafenamide without dolutegravir (1·33, 1·15-1·53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1·79, 1·52-2·11, and 1·70, 1·44-2·01, respectively). INTERPRETATION: Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. FUNDING: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.</p
Nonopportunistic infection leading to rapidly progressive dementia in a patient with HIV/AIDS
No full textDesign of high-performance E-band SPDT switch and LNA in 0.13 μm SiGe BiCMOS technology
No full textThis paper presents the design of high-performance E-band single-pole double-through (SPDT) switch and low noise amplifier (LNA) as a part of transceiver front-end in an 0.13 μm SiGe BiCMOS technology. The quarter-wave shunt SPDT switch is designed using reverse-saturated SiGe HBTs. The resulting switch exhibits an insertion loss of 2.1 dB, isolation of 26 dB, reflection coefficient better than 18 dB at 75 GHz and provides a bandwidth of more than 35 GHz. The designed switch is integrated with a single-in differential-output (SIDO) low noise amplifier (LNA) and utilized as input matching element of the LNA. The LNA utilizes a common-emitter amplifier at the first stage and a casocode amplifier at the second stage to exploit the advantages of both common-emitter and cascode topologies. The resulting LNA with integrated switch achieves a gain and noise figure(NF) of 26 dB and 6.9 dB, respectively at 75 GHz with a 3 dB bandwidth of 12 GHz. Output referred 1-dB compression point of +5.5 dBm is achieved at 75 GHz. The designed integrated block consumes 45.5 mW of DC power and occupies an area of 720 μm × 580 μm excluding RF pads.Peer reviewe
The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-na
No full textThe relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-na < ve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied. Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported. No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of < 25 mu mol/l. The great majority of treatment-na < ve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-na < ve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy
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