Biomarkers for NeuroAIDS: The Widening Scope of Metabolomics

Pendyala, Gurudutt; Want, Elizabeth J.; Webb, William R.; Siuzdak, Gary; Fox, Howard S.

doi:10.1007/s11481-006-9041-3

Cited by 33 publications

(22 citation statements)

References 74 publications

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“…NMR ( 1 H-NMR) advantages include the theoretical possibility to detect and structurally elucidate any molecule containing hydrogen and also being very quantitative in its nature. Disadvantages include low sensitivity, typical detection limits are in the range milli-to high micromolar (Pendyala et al 2007), and also the fact that one-dimensional spectra gets very dense with spectral information resulting in more abundant metabolites masking signal of less abundant ones. Mass spectrometry advantages include high sensitivity (milli-to nanomolar) and being easily interfaced with chromatography resulting in the capability to temporally resolve the analysis of thousands of components.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics: Moving to the Clinic

Nordström

Lewensohn

2009

J Neuroimmune Pharmacol

142

109

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Assessment of a biological system by means of global and non-targeted metabolite profiling--metabolomics or metabonomics--provides the investigator with molecular information that is close to the phenotype in question in the sense that metabolites are an ultimate product of gene, mRNA, and protein activity. Over the last few years, there has been a rapidly growing number of metabolomics applications aimed at finding biomarkers which could assist diagnosis, provide therapy guidance, and evaluate response to therapy for particular diseases. Also, within the fields of drug discovery, drug toxicology, and personalized pharmacology, metabolomics is emerging as a powerful tool. This review seeks to update the reader on analytical strategies, biomarker findings, and implications of metabolomics for the clinic. Particular attention is paid to recent biomarkers found related to neurological, cardiovascular, and cancer diseases. Moreover, the impact of metabolomics in the drug discovery and development process is examined.

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Section: Discussionmentioning

confidence: 99%

Metabolomics: Moving to the Clinic

Nordström

Lewensohn

2009

J Neuroimmune Pharmacol

142

109

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“…In their study, Riddler et al 40 demonstrated through CD4 cell count and viral load that most patients in this study were not defined as having AIDS and were therefore relatively healthy, with CD4 cell counts of above 600 cells per mm. 3 These authors therefore concluded that the majority of metabolites (organic acids) identified as being associated with HIV-induced mitochondrial damage was not associated with disease progression. The bigger problem for commenting on disease progression and associated metabolites is that the identified metabolites have not yet been quantified.…”

Section: Impact Of Metabolites On Disease Progressionmentioning

confidence: 99%

“…3,10 Metabonomics on the other hand measures the global, dynamic changes in metabolic profiles of a biological system in response to disease, drugs, etc. 3,10 For the purpose of this review, metabonomics is used to mean detecting metabolites or profiles affected by HIV/AIDS and/or its treatment. This article first sets the stage by confirming metabolic changes as a consequence of HIV infection, virus induced immune deficiency and/or HAART with acknowledgement that the largest amount of existing knowledge about HIV/AIDS related metabolic abnormalities was collected by conventional biochemical methodologies.…”

Section: Introductionmentioning

confidence: 99%

Metabonomic analysis of HIV-infected biofluids

2013

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Monitoring the progression of HIV infection to full-blown acquired immune deficiency syndrome (AIDS) and assessing responses to treatment will benefit greatly from the identification of novel biological markers especially since existing clinical indicators of disease are not infallible. Nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) are powerful methodologies used in metabonomic analyses for an approximation of HIV-induced changes to the phenotype of an infected individual. Although early in its application to HIV/AIDS, (biofluid) metabonomics has already identified metabolic pathways influenced by both HIV and/or its treatment. To date, biofluid NMR and MS data show that the virus and highly active antiretroviral treatment (HAART) mainly influence carbohydrate and lipid metabolism, suggesting that infected individuals are susceptible to very specific metabolic complications. A number of well-defined biofluid metabonomic studies clearly distinguished HIV negative, positive and treatment experienced patient profiles from one another. While many of the virus or treatment affected metabolites have been identified, the metabonomics measurements were mostly qualitative. The identities of the molecules were not always validated neither were the statistical models used to distinguish between groups. Assigning particular metabolic changes to specific drug regimens using metabonomics also remains to be done. Studies exist where identified metabolites have been linked to various disease states suggesting great potential for the use of metabonomics in disease prognostics. This review therefore examines the field of metabonomics in the context of HIV/AIDS, comments on metabolites routinely detected as being affected by the pathogen or treatment, explains what existing data suggest and makes recommendations on future research.

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“…Such biomarker(s) will help in early detection and classification of neurocognitive impairment. 24 Furthermore, multiple reaction monitoring (MRM) 25 can also be applied to drug discovery assays in the context of HIV-1 infection of macrophages and can be used for lead selection, lead optimization, in vivo efficacy screening, and early in vivo toxicological testing. This targeted metabolomics platform can be utilized in the future as a high-throughput screening tool for identification of new biomarker(s) in plasma and CSF of HIV-1 infected individuals.…”

Section: Introductionmentioning

confidence: 99%

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

et al. 2016

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HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages.We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation.The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of a-ketoglutarate (a-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, a-KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages.Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS.

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Biomarkers for NeuroAIDS: The Widening Scope of Metabolomics

Cited by 33 publications

References 74 publications

Metabolomics: Moving to the Clinic

Metabolomics: Moving to the Clinic

Metabonomic analysis of HIV-infected biofluids

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

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