Following the elite: Targeting immunometabolism to limit HIV pathogenesis.
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ABSTRACT:
SUBMITTER: Routy JP
PROVIDER: S-EPMC6491710 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Following the elite: Targeting immunometabolism to limit HIV pathogenesis.
Routy Jean-Pierre JP Isnard Stéphane S Ramendra Rayoun R
EBioMedicine 20190322
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Project description:BackgroundApproximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control.MethodsPlasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n = 8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n = 8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response.FindingsOur data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs.InterpretationAll these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. FUND: This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness.
| S-EPMC6491381 | biostudies-literature
Project description:We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.
| S-EPMC8242259 | biostudies-literature
Project description:The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
| S-EPMC7118080 | biostudies-literature
Project description:Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (<20 copies/106 CD4+ T-cells) without evidence of replication-competent viruses (<0.025 IUPM), consistent with high levels of defective genomes, strong cellular HIV-1-specific immune response, and a high poly-functionality index (>0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (<0.01 s/n) in env gene than other EC. We postulate that these EEC represent cases of spontaneous functional HIV-1 cure. A non-functional and non-genetically evolving viral reservoir along with an HIV-1-specific immune response seems to be key for the spontaneous functional cure.
| S-EPMC7002478 | biostudies-literature
Project description:It is well known that aging is associated with dysregulated metabolism. This is seen both in terms of systemic metabolism, as well as at the cellular level with clear mitochondrial dysfunction. More recently, the importance of cellular metabolism in immune cells, or immunometabolism, has been highlighted as a major modifier of immune cell function. Indeed, T cell activation, differentiation, and effector function partly depend on alterations in metabolic pathways with different cell types and functionality favoring either glycolysis or oxidative phosphorylation. While immune system dysfunction with aging is well described, what remains less elucidated is how the integral networks that control immune cell metabolism are specifically affected by age. In recent years, this significant gap has been identified and work has begun to investigate the various ways immunometabolism could be impacted by both chronological age and age-associated symptoms, such as the systemic accumulation of senescent cells. Here, in this mini-review, we will examine immunometabolism with a focus on T cells, aging, and interventions, such as mTOR modulators and senolytics. This review also covers a timely perspective on how immunometabolism may be an ideal target for immunomodulation with aging.
| S-EPMC8334863 | biostudies-literature
Project description:BackgroundHIV Elite Controllers may reveal insights into virus persistence given they harbour small reservoir sizes, akin to HIV non-controllers treated early with combination antiretroviral therapy. Both groups of patients represent the most promising candidates for interventions aimed at sustained remission or 'cure'. Analytic treatment interruption (ATI) in the latter group leads to stochastic rebound of virus, though it is unclear whether loss of elite control is also associated with similar rebound characteristics.MethodsWe studied three discrete periods of virus rebound during myeloma related immune disruption over 2.5 years in an elite controller who previously underwent autologous stem cell transplantation (ASCT) in the absence of any antiretroviral therapy. Single genome sequencing of the V1-V4 region of env in PBMC and plasma was performed and phylogenies reconstructed. Average pairwise distance (APD) was calculated and non-parametric methods used to assess compartmentalisation. Coreceptor usage was predicted based on genotypic algorithms.Results122 single genome sequences were obtained (median 26 sequences per rebound). The initial rebounding plasma env sequences following ASCT represented two distinct lineages, and clustered with proviral DNA sequences isolated prior to ASCT. One of the lineages was monophyletic, possibly indicating reactivation from clonally expanded cells. The second rebound occurred 470 days after spontaneous control of the first rebound and was phylogenetically distinct from the first, confirmed by compartmentalisation analysis, with a different cellular origin rather than ongoing replication. By contrast, third rebound viruses clustered with second rebound viruses, with evidence for ongoing evolution that was associated with lymphopenia and myeloma progression. Following ASCT a shift in tropism from CXCR4-tropic viruses to a CCR5-tropic population was observed to persist through to the third rebound.ConclusionsOur data highlight similarities in the viral reservoir between elite and non-controllers undergoing ATI following allogeneic transplantation. The lack of propagation of CXCR4 using viruses following transplantation warrants further study.
| S-EPMC4942039 | biostudies-literature
Project description:BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.
| S-EPMC11014653 | biostudies-literature
Project description:Elite controllers maintain HIV-1 viral loads below the limit of detection. The mechanisms responsible for this phenomenon are poorly understood. As microRNAs (miRNAs) are regulators of gene expression and some of them modulate HIV infection, we have studied the miRNA profile in plasma from HIV elite controllers and chronically infected individuals and compared against healthy donors. Several miRNAs correlate with CD4+ T cell count or with the known time of infection. No significant differences were observed between elite controllers and healthy donors; however, 16 miRNAs were different in the plasma of chronic infected versus healthy donors. In addition, levels of hsa-miR-29b-3p, hsa-miR-33a-5p and hsa-miR-146a-5p were higher in plasma from elite controllers than chronic infected and hsa-miR-29b-3p and hsa-miR-33a-5p overexpression significantly reduced the viral production in MT2 cells. Therefore, levels of circulating miRNAs might be of diagnostic and/or prognostic value for HIV infection. Additionally, hsa-miR-29b-3p and miR-33a-5p may be used in therapeutic strategies.
2014-08-04 | GSE58868 | GEO
Project description:CD4 receptor molecules on 'T' lymphocytes and macrophages have already been identified as the route of entry for HIV. However CCR5 and CXCR4 are identified only recently as the second receptors for HIV on macrophages and 'T' lymphocytes respectively. Presence of homozygous CCR5 Δ 32, a defective CCR5 gene leads to resistance to HIV infection in the risk groups. While heterozygous CCRS Δ 32 leads to delay in the progress of HIV infection to AIDS.
| S-EPMC5531965 | biostudies-other
Project description:Elite controllers maintain HIV-1 viral loads below the limit of detection. The mechanisms responsible for this phenomenon are poorly understood. As microRNAs (miRNAs) are regulators of gene expression and some of them modulate HIV infection, we have studied the miRNA profile in plasma from HIV elite controllers and chronically infected individuals and compared against healthy donors. Several miRNAs correlate with CD4+ T cell count or with the known time of infection. No significant differences were observed between elite controllers and healthy donors; however, 16 miRNAs were different in the plasma of chronic infected versus healthy donors. In addition, levels of hsa-miR-29b-3p, hsa-miR-33a-5p and hsa-miR-146a-5p were higher in plasma from elite controllers than chronic infected and hsa-miR-29b-3p and hsa-miR-33a-5p overexpression significantly reduced the viral production in MT2 cells. Therefore, levels of circulating miRNAs might be of diagnostic and/or prognostic value for HIV infection. Additionally, hsa-miR-29b-3p and miR-33a-5p may be used in therapeutic strategies. An exploratory cross-sectional study of microRNA levels in EDTA plasma samples. Plasma samples were obtained from 24 subjects and were classified in 3 groups, 9 Elite Controllers (defined as individuals with plasma viral load (PVL) < 50 copies/ml, CD4 count >350/ml), 9 chronic HIV patients (CH) under anti-retroviral treatment and 6 healthy HIV negative donors (HD). This study was approved by the HuM-CM-)sped Foundation Ethics Committee and informed consent was obtained from all subjects.
2014-08-04 | E-GEOD-58868 | biostudies-arrayexpress