Trans Cohorts Metabolomic Modulation Following Long-Term Successful Therapy in HIV-Infection

Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic adaptation in people living with HIV (PLWH). The successful short-term cART reported abnormalities in the metabolic reprogramming in PLWH, but the long-term consequences are unknown. This study investigated alterations in the plasma metabolic profiles by comparing PLWH and matched HIV-negative controls (HC) from Cameroon and India. We used untargeted and targeted LC-MS/MS-based metabolic profiling in PLWH with long-term (>5years) successful therapy in a trans cohorts approach. Advanced statistical and bioinformatics analyses showed altered amino acid metabolism, more specifically to glutaminolysis in PLWH with therapy than HIV-negative controls that can lead to excitotoxicity in both the cohorts. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. The modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells. Our patient-based metabolomics and in vitro study, therefore, highlight the importance of altered glutaminolysis in PLWH that can be linked accelerated neurocognitive aging and metabolic reprogramming in latently infected cells.

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Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection

Communications Biology ◽

10.1038/s42003-021-02985-3 ◽

2022 ◽

Vol 5 (1) ◽

Author(s):

Flora Mikaeloff ◽

Sara Svensson Akusjärvi ◽

George Mondinde Ikomey ◽

Shuba Krishnan ◽

Maike Sperk ◽

...

Keyword(s):

Hiv Infection ◽

Cell Model ◽

Antiretroviral Drugs ◽

Metabolic Reprogramming ◽

System Level ◽

People Living With Hiv ◽

Low Grade ◽

Middle Income ◽

Living With Hiv

AbstractDespite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. Using untargeted and targeted LC-MS/MS-based metabolic profiling and applying advanced system biology methods, an altered amino acid metabolism, more specifically to glutaminolysis in PLWH than HC were reported. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. Further, modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells.

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Excess burden of age-associated comorbidities among people living with HIV in British Columbia, Canada: a population-based cohort study

BMJ Open ◽

10.1136/bmjopen-2020-041734 ◽

2021 ◽

Vol 11 (1) ◽

pp. e041734

Author(s):

Ni Gusti Ayu Nanditha ◽

Adrianna Paiero ◽

Hiwot M Tafessu ◽

Martin St-Jean ◽

Taylor McLinden ◽

...

Keyword(s):

British Columbia ◽

Cohort Study ◽

Population Based ◽

Age At Diagnosis ◽

Secondary Outcome ◽

People Living With Hiv ◽

Prevalence Trends ◽

Living With Hiv ◽

Negative Controls ◽

Hiv Negative

ObjectivesAs people living with HIV (PLWH) live longer, morbidity and mortality from non-AIDS comorbidities have emerged as major concerns. Our objective was to compare prevalence trends and age at diagnosis of nine chronic age-associated comorbidities between individuals living with and without HIV.Design and settingThis population-based cohort study used longitudinal cohort data from all diagnosed antiretroviral-treated PLWH and 1:4 age-sex-matched HIV-negative individuals in British Columbia, Canada.ParticipantsThe study included 8031 antiretroviral-treated PLWH and 32 124 HIV-negative controls (median age 40 years, 82% men). Eligible participants were ≥19 years old and followed for ≥1 year during 2000 to 2012.Primary and secondary outcome measuresThe presence of non-AIDS-defining cancers, diabetes, osteoarthritis, hypertension, Alzheimer’s and/or non-HIV-related dementia, cardiovascular, kidney, liver and lung diseases were identified from provincial administrative databases. Beta regression assessed annual age-sex-standardised prevalence trends and Kruskal-Wallis tests compared the age at diagnosis of comorbidities stratified by rate of healthcare encounters.ResultsAcross study period, the prevalence of all chronic age-associated comorbidities, except hypertension, were higher among PLWH compared with their community-based HIV-negative counterparts; as much as 10 times higher for liver diseases (25.3% vs 2.1%, p value<0.0001). On stratification by healthcare encounter rates, PLWH experienced most chronic age-associated significantly earlier than HIV-negative controls, as early as 21 years earlier for Alzheimer’s and/or dementia.ConclusionsPLWH experienced higher prevalence and earlier age at diagnosis of non-AIDS comorbidities than their HIV-negative controls. These results stress the need for optimised screening for comorbidities at earlier ages among PLWH, and a comprehensive HIV care model that integrates prevention and treatment of chronic age-associated conditions. Additionally, the robust methodology developed in this study, which addresses concerns on the use of administrative health data to measure prevalence and incidence, is reproducible to other settings.

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Metabolic Reprogramming and Molecular Rewiring in Cancer: Therapeutic Opportunities

The Indonesian Biomedical Journal ◽

10.18585/inabj.v13i2.1598 ◽

2021 ◽

Vol 13 (2) ◽

pp. 114-39

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Cancer Cells ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Term Survival ◽

Metabolic Remodeling ◽

New Strategy ◽

Epigenetic Remodeling ◽

Altered Metabolism

BACKGROUND: A lot of contemporary cancer research has concentrated on genetic influence. However, cancer also involves biochemical changes, such as metabolic adaptation to support the aberrant cell proliferation.CONTENT: The fast cell proliferation in cancer cells enforce a metabolic re-arrangement to promote their long-term survival. The increased glucose uptake and fermentation of glucose to lactate are common features of this altered metabolism known as “the Warburg effect”. These metabolic pathways regulation enable cancer cells to produce adenosine triphosphate (ATP) in an efficient way. Epigenetic and metabolic changes also both affect molecular rewiring in cancer cells and promote cancer development and progression.SUMMARY: Metabolic rewiring and epigenetic remodeling establishing a direct link between metabolism and nuclear transcription to promote the survival of tumor cells. A further understanding of how metabolic remodeling can result in epigenetic changes in tumors, affecting cancer cell differentiation, proliferation, and/or apoptosis, will lead to a new strategy for cancer therapy.KEYWORDS: cancer metabolism, epigenetics, metabolic reprogramming, molecular rewiring

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Cognitive function, depressive symptoms and syphilis in HIV-positive and HIV-negative individuals

International Journal of STD & AIDS ◽

10.1177/0956462418817612 ◽

2019 ◽

Vol 30 (5) ◽

pp. 440-446 ◽

Cited By ~ 2

Author(s):

Davide De Francesco ◽

Alan Winston ◽

Jonathan Underwood ◽

Fiona V Cresswell ◽

Jane Anderson ◽

...

Keyword(s):

Depressive Symptoms ◽

Cognitive Function ◽

Cognitive Test ◽

People Living With Hiv ◽

Serological Tests ◽

Syphilis Infection ◽

Patient Health ◽

History Of ◽

Negative Controls ◽

Hiv Negative

We evaluated associations between history of syphilis infection and both cognitive function and depressive symptoms in people living with HIV (PLHIV) and comparable HIV-negative controls. Syphilis serological tests, cognitive function and depression were assessed in PLHIV and controls participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study. Cognitive test scores were converted to demographically adjusted T-scores (mean = 50, SD = 10) and then averaged to obtain a global T-score. Severity of depressive symptoms was assessed via the Patient Health Questionnaire-9. Associations of syphilis with global T-scores and depression were assessed using median regression. The 623 PLHIV and 246 HIV-negative controls were predominantly male (89.3% and 66.5%) with median age (interquartile range [IQR]) of 57 (53–63) and 58 (53–63) years, respectively. PLHIV had lower global cognitive T-scores (median [IQR] 48.7 [45.1, 52.1] versus 50.5 [47.0, 53.9], p < 0.001), more severe depressive symptoms (median [IQR] 4 [1, 10] versus 1 [0, 3], p < 0.001) and were more likely to report history of syphilis infection (22.0% versus 8.1%) than controls. There was no significant association between history of syphilis and global cognitive function in either PLHIV (p = 0.69) or controls (p = 0.10). Participants with a history of syphilis had more severe depressive symptoms (median [IQR] 4 [1, 9] versus 2 [0, 8], p = 0.03); however, the association became non-significant (p = 0.62) after adjusting for HIV status and potential confounders. Despite the higher prevalence of syphilis infection in PLHIV, there was no evidence of an association between history of syphilis infection and impaired cognitive function nor depressive symptoms after accounting for potential confounders.

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Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV-negative controls

HIV Medicine ◽

10.1111/hiv.12714 ◽

2019 ◽

Vol 20 (4) ◽

pp. 274-285 ◽

Cited By ~ 6

Author(s):

D De Francesco ◽

J Underwood ◽

E Bagkeris ◽

M Boffito ◽

FA Post ◽

...

Keyword(s):

Cognitive Function ◽

Lifestyle Factors ◽

People Living With Hiv ◽

Living With Hiv ◽

Negative Controls ◽

Hiv Negative

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Evolution of Serum Acute-Phase Glycoproteins Assessed by 1H-NMR in HIV Elite Controllers

Frontiers in Immunology ◽

10.3389/fimmu.2021.730691 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ana-Irene Malo ◽

Joaquim Peraire ◽

Ezequiel Ruiz-Mateos ◽

Jenifer Masip ◽

Núria Amigó ◽

...

Keyword(s):

Acute Phase ◽

Proton Nuclear Magnetic Resonance ◽

People Living With Hiv ◽

Low Grade ◽

Elite Controllers ◽

Viral Control ◽

H Nmr ◽

Inflammatory State ◽

Over Time ◽

Hiv Negative

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) who maintain undetectable viral loads (VLs) despite not being on antiretroviral therapy (ART). However, this phenotype is heterogeneous, with some of these subjects losing virological control over time. In this longitudinal retrospective study, serum acute-phase glycoprotein profile assessed by proton nuclear magnetic resonance (1H-NMR) was determined in 11 transient controllers (TCs) who spontaneously lost virological control and 11 persistent controllers (PCs) who persistently maintained virological control over time. Both PCs and TCs showed similar acute-phase glycoprotein profiles, even when TCs lost the virological control (GlycB, p = 0.824 and GlycA, p = 0.710), and the serum acute-phase glycoprotein signature in PCs did not differ from that in HIV-negative subjects (GlycB, p = 0.151 and GlycA, p = 0.243). Differences in serum glycoproteins A and B were significant only in ECs compared to HIV-typical progressors (TPs) with < 100 CD4+ T-cells (p < 0.001). 1H-NMR acute-phase glycoprotein profile does not distinguish TCs form PCs before the loss of viral control. ECs maintain a low-grade inflammatory state compared to TPs. PCs revealed a closer serum signature to HIV-negative subjects, reaffirming this phenotype as a closer model of functional control of HIV.

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Electrocardiographic and echocardiographic abnormalities in urban African people living with HIV in South Africa

PLoS ONE ◽

10.1371/journal.pone.0244742 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0244742

Author(s):

Geert V. T. Roozen ◽

Ruchika Meel ◽

Joyce Peper ◽

William D. F. Venter ◽

Roos E. Barth ◽

...

Keyword(s):

South Africa ◽

Viral Load ◽

Left Ventricular Mass ◽

Qt Interval ◽

Left Ventricular ◽

Hiv Positive ◽

People Living With Hiv ◽

Living With Hiv ◽

Negative Controls ◽

Hiv Negative

Background Studies from high income countries report that HIV-positive people have an impaired systolic and diastolic cardiac function compared to HIV-negative people. It is unclear if results can be translated directly to the Sub-Saharan Africa context. This study assesses electro- and echocardiographic characteristics in an urban African population, comparing HIV-positive people (treated and not yet treated) with HIV-negative controls. Methods We conducted a cross-sectional study in Johannesburg, South Africa. We enrolled HIV-positive participants from three randomized controlled trials that had recruited participants from routine HIV testing programs. HIV-negative controls were recruited from the community. Data were collected on demographics, cardiovascular risk factors, medical history and electrocardiographic and echocardiographic characteristics. Results In total, 394 HIV-positive participants and 153 controls were enrolled. The mean age of HIV-positive participants was 40±9 years (controls: 35±10 years), and 34% were male (controls: 50%). Of HIV-positive participants 36% were overweight or obese (controls: 44%), 23% had hypertension (controls: 28%) and 12% were current smoker (controls: 37%). Median time since HIV diagnosis was 6.0 years (IQR 2.3–10.0) and median treatment duration was 4.0 years (IQR 0.0–8.0), 50% had undetectable viral load. The frequency of anatomical cardiac abnormalities was low and did not differ between people with and without HIV. We observed no relation between HIV or anti-retroviral therapy (ART) and systolic or diastolic heart function. There was an association between ART use and corrected QT interval: +11.8 ms compared to HIV-negative controls (p<0.01) and +18.9 ms compared to ART-naïve participants (p = 0.01). We also observed a higher left ventricular mass index in participants on ART (+7.8 g/m2, p<0.01), but this association disappeared after adjusting for CD4 cell count, viral load and HIV-duration. Conclusion The low number of major cardiac abnormalities in this relatively young, well managed urban African HIV-positive population is reassuring. The increase in corrected QT interval and left ventricular mass may contribute to higher cardiac mortality and morbidity in people living with HIV in the long term.

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A study of bone mineral density among people living with HIV in India and its correlation with CD4 count

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20170153 ◽

2017 ◽

Vol 5 (2) ◽

pp. 563 ◽

Cited By ~ 2

Author(s):

Kamal K. Sawlani ◽

Sushrut Singh ◽

Shyam C. Chaudhary ◽

D. Himanshu Reddy ◽

Kauser Usman ◽

...

Keyword(s):

Cd4 Count ◽

Hiv Positive ◽

Control Group ◽

People Living With Hiv ◽

Care Hospital ◽

Mineral Density ◽

Hiv Patients ◽

Negative Controls ◽

Prevalence Of Osteoporosis ◽

Hiv Negative

Background: Data on the prevalence of osteoporosis in HIV patients in Asian population is scarce this study was done to find out the prevalence of osteoporosis in HIV infected patients and its correlation with CD4 counts.Methods: This cross- sectional study was conducted in NACO- ART center of tertiary care hospital. Total 115 HIV patients were included in this study which were divided into ART naive (n= 69) and patients taking ART (n= 46). We analysed BMD by DEXA in 115 HIV positive patients and 78 HIV negative age and sex matched controls. Correlation of BMD with a CD4 count and ART regimen was studied.Results: BMD was found to be low in HIV positive patients. T score in HIV positive patients was significantly lower (p<0.05) as compared to the HIV negative control group. The prevalence of osteopenia and osteoporosis in HIV positive patients was 50.4% and 29.6% respectively, as compared to 23.1% and 2.6% in HIV negative controls. BMD showed relation with CD4 count. We did not find any statistical difference between any ART regimen and BMD.Conclusions: The prevalence of osteopenia and osteoporosis in HIV infected cases was higher as compared to HIV negative controls and higher in ART group as compared to ART naïve group. Low BMD levels show correlation with low CD4 count. We recommend that HIV positive patients especially with advanced stage of disease, low CD4 count should be screened for low BMD by DEXA scan for osteoporosis and managed accordingly

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Beyond Il-5: Metabolic Reprogramming and Stromal Support Are Prerequisite for Generation and Survival of Long-Lived Eosinophil

Cells ◽

10.3390/cells10040815 ◽

2021 ◽

Vol 10 (4) ◽

pp. 815

Author(s):

Mackenzie E. Coden ◽

Matthew T. Walker ◽

Brian M. Jeong ◽

Andrew R. Connelly ◽

Reina Nagasaka ◽

...

Keyword(s):

Bone Marrow ◽

Ex Vivo ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Key Factors ◽

Large Numbers ◽

Stromal Support ◽

Health And Disease ◽

Novel Method

Eosinophils play surprisingly diverse roles in health and disease. Accordingly, we have now begun to appreciate the scope of the functional and phenotypic heterogeneity and plasticity of these cells. Along with tissue-recruited subsets during inflammation, there are tissue resident eosinophil phenotypes with potentially longer life spans and less dependency on IL-5 for survival. Current models to study murine eosinophils ex vivo rely on IL-5-sustained expansion of eosinophils from bone marrow hematopoietic progenitors. Although it does generate eosinophils (bmEos) in high purity, such systems are short-lived (14 days on average) and depend on IL-5. In this report, we present a novel method of differentiating large numbers of pure bone marrow-derived eosinophils with a long-lived phenotype (llEos) (40 days on average) that require IL-5 for initial differentiation, but not for subsequent survival. We identified two key factors in the development of llEos: metabolic adaptation and reprogramming induced by suppressed nutrient intake during active differentiation (from Day 7 of culture), and interaction with IL-5-primed stromal cells for the remainder of the protocol. This regimen results in a higher yield and viability of mature eosinophils. Phenotypically, llEos develop as Siglec-F(+)Ly6G(+) cells transitioning to Siglec-F(+) only, and exhibit typical eosinophil features with red eosin granular staining, as well as the ability to chemotax to eotaxin Ccl11 and process fibrinogen. This culture system requires less reagent input and allows us to study eosinophils long-term, which is a significant improvement over IL-5-driven differentiation protocols. Moreover, it provides important insights into factors governing eosinophil plasticity and the ability to assume long-lived IL-5-independent phenotypes.

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CTN 328: immunogenicity outcomes in people living with HIV in Canada following vaccination for COVID-19 (HIV-COV): protocol for an observational cohort study

BMJ Open ◽

10.1136/bmjopen-2021-054208 ◽

2021 ◽

Vol 11 (12) ◽

pp. e054208

Author(s):

Cecilia T Costiniuk ◽

Joel Singer ◽

Marc-André Langlois ◽

Iva Kulic ◽

Judy Needham ◽

...

Keyword(s):

Cohort Study ◽

Immune Responses ◽

Guideline Development ◽

Vaccine Dose ◽

People Living With Hiv ◽

Similar Time ◽

Dosing Strategies ◽

Living With Hiv ◽

Negative Controls ◽

Hiv Negative

IntroductionMost existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH.Methods and analysisThis multicentred observational Canadian cohort study will enrol 400 PLWH aged >16 years from Montreal, Ottawa, Toronto and Vancouver. Subpopulations of PLWH of interest will include individuals: (1) >55 years of age; (2) with CD4 counts <350 cells/mm3; (3) with multimorbidity (>2 comorbidities) and (4) ‘stable’ or ‘reference’ PLWH (CD4 T cells >350 cells/mm3, suppressed viral load for >6 months and <1 comorbidity). Data for 1000 HIV-negative controls will be obtained via a parallel cohort study (Stop the Spread Ottawa), using similar time points and methods. Participants receiving >1 COVID-19 vaccine will attend five visits: prevaccination; 1 month following the first vaccine dose; and at 3, 6 and 12 months following the second vaccine dose. The primary end point will be the percentage of PLWH with COVID-19-specific antibodies at 6 months following the second vaccine dose. Humoral and cell-mediated immune responses, and the interplay between T cell phenotypes and inflammatory markers, will be described. Regression techniques will be used to compare COVID-19-specific immune responses to determine whether there are differences between the ‘unstable’ PLWH group (CD4 <350 cells/mm3), the stable PLWH cohort and the HIV-negative controls, adjusting for factors believed to be associated with immune response. Unadjusted analyses will reveal whether there are differences in driving factors associated with group membership.Ethics and disseminationResearch ethics boards at all participating institutions have granted ethics approval for this study. Written informed consent will be obtained from all study participants prior to enrolment. The findings will inform the design of future COVID-19 clinical trials, dosing strategies aimed to improve immune responses and guideline development for PLWH.Trial registration numberNCT04894448.

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