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Qualitative serum organic acid profiles of HIV-infected individuals not on antiretroviral treatment

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Abstract

The first application of gas chromatography mass spectrometry (GC–MS) metabolomics to the analysis of organic acid profiles in sera of asymptomatic human immunodeficiency virus (HIV)-infected individuals (n = 18) compared to uninfected controls (n = 21), is reported here. Several organic acids are well-established diagnostic biomarkers of mitochondrial dysfunction, making the analysis of the organic acid metabolome well suited to monitoring the progressive disruption of mitochondrial structure and function during HIV infection. Using a multifaceted analytical-bioinformatics procedure, at least 10 of these metabolites could be linked to (1) disrupted mitochondrial metabolism, (2) changes in lipid metabolism and (3) oxidative stress, all of which are aberrations caused by HIV infection. Because of the role of the mitochondria in apoptosis, higher levels of this type of cell death in infected (compared to uninfected) individuals was used to support GC–MS data. This study demonstrates that mass spectrometry metabolomics detects biomarkers of mitochondrial dysfunction which could potentially be developed into indicators of HIV infection, perhaps also to monitor disease progression and the response to antiretroviral treatment.

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References

  • Banda, N. K., Bernier, J., Kurahara, D. K., et al. (1992). Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. Journal of Experimental Medicine, 176, 1099–1106.

    Article  PubMed  CAS  Google Scholar 

  • Barker, M., & Rayens, W. (2003). Partial least squares for discrimination. Journal of Chemometrics, 17, 166–173.

    Article  CAS  Google Scholar 

  • Barshop, B. A. (2004). Metabolomic approaches to mitochondrial disease: correlation of urine organic acids. Mitochondrion, 4, 521–527.

    Article  PubMed  CAS  Google Scholar 

  • Bjorkhem, I., & Diczfalusy, U. (2002). Oxysterols: Friends, foes, or just fellow passengers? Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 734–742.

    Article  PubMed  CAS  Google Scholar 

  • Broeckling, C. D., Reddy, I. R., Duran, A. L., Zhao, X., & Sumner, L. W. (2006). MET-IDEA: Data extraction tool for mass spectrometry-based metabolomics. Analytical Chemistry, 78, 4334–4341.

    Article  PubMed  CAS  Google Scholar 

  • Calabrese, L. H., Proffitt, M. R., Gupta, M. K., et al. (1984). Serum beta 2-microglobulin and interferon in homosexual males: Relationship to clinical findings and serologic status to the human T lymphotropic virus (HTLV-III). AIDS Research, 1, 423–438.

    Article  PubMed  Google Scholar 

  • Calza, L., Manfredi, R., & Chiodo, F. (2003). Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management. International Journal of Antimicrobial Agents, 22, 89–99.

    Article  PubMed  CAS  Google Scholar 

  • Centlivre, M., Sala, M., Wain-Hobson, S., & Berkhout, B. (2007). In HIV-1 pathogenesis the die is cast during primary infection. Acquired Immuno Deficiency Syndrome, 21, 1–11.

    Google Scholar 

  • Dunn, W. B., Broadhurst, D., Begley, P., et al. (2011). Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nature Protocols, 6, 1060–1083.

    Article  PubMed  CAS  Google Scholar 

  • Duran, M. (2005). Disorders of mitochondrial fatty acid oxidation. In N. Blau, M. Duran, & M. E. Blaskovics (Eds.), Physician’s guide to the laboratory diagnosis of metabolic diseases (Revised 2nd ed., pp. 309–334). Heidelberg: Springer-Verlag.

  • Gkrania-Klotsas, E., & Klotsas, A. (2007). HIV and HIV treatment: effects on fats, glucose and lipids. British Medical Bulletin, 84, 49–68.

    Article  PubMed  Google Scholar 

  • Grunfeld, C., & Kotler, D. P. (1992). Wasting in the acquired immunodeficiency syndrome. Seminars in Liver Disease, 12, 175–187.

    Article  PubMed  CAS  Google Scholar 

  • Grunfeld, C., Kotler, D. P., Hamadeh, R., Tierney, A., Wang, J., & Pierson, R. N. (1989). Hypertriglyceridemia in the acquired immunodeficiency syndrome. American Journal of Medicine, 86, 27–31.

    Article  PubMed  CAS  Google Scholar 

  • Grunfeld, C., Pang, M., Doerrler, W., Shigenaga, J. K., Jensen, P., & Feingold, K. R. (1992). Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Journal of Clinical Endocrinology and Metabolism, 74, 1045–1052.

    Article  PubMed  CAS  Google Scholar 

  • Guzmán, M., Lo Verme, J., Fu, J., Oveisi, F., Blázquez, C., & Piomelli, D. (2004). Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPAR-α). Journal of Biological Chemistry, 279, 27849–27854.

    Article  PubMed  Google Scholar 

  • Hattingh, Z., Walsh, C., Veldman, F. J., & Bester, C. J. (2009). Metabolic profile of HIV-infected women in Mangaung, Free State. South African Journal of Clinical Nutrition, 22, 23–28.

    Google Scholar 

  • Hewer, R., Vorster, J., Steffens, F. E., & Meyer, D. (2006). Applying biofluid 1H NMR-based metabonomic techniques to distinguish between HIV-1 positive/AIDS patients on antiretroviral treatment and HIV-1 negative individuals. Journal of Pharmaceutical and Biomedical Analysis, 41, 1442–1446.

    Article  PubMed  CAS  Google Scholar 

  • Hoffman, G. F., & Feyh, P. (2005). Organic acid analysis. In N. Blau, M. Duran, & M. E. Blaskovics (Eds), Physician’s guide to the laboratory diagnosis of metabolic diseases (Revised 2nd ed., pp. 27–44). Heidelberg: Springer-Verlag.

  • Hommes, M. J. T., Romijn, J. A., Godfried, M. H., et al. (1990). Increased resting energy expenditure in human immunodeficiency virus-infected men. Metabolism and Clinical Nutrition, 39, 1186–1190.

    CAS  Google Scholar 

  • Iuliano, L., Micheletta, F., Natoli, S., et al. (2003). Measurement of oxysterols and alpha-tocopherol in plasma and tissue samples as indices of oxidant stress status. Analytical Biochemistry, 312, 217–223.

    Article  PubMed  CAS  Google Scholar 

  • Jansen, C. A., van Baarle, D., & Miedema, F. (2006). HIV-specific CD4+ T cells and viremia: Who’s in control? Trends in Immunology, 27, 119–124.

    Article  PubMed  CAS  Google Scholar 

  • Jellum, E., Kluge, T., Borresen, H. C., Stokke, O., & Eldjarn, L. (1970). Pyroglutamic aciduria—A new inborn error of metabolism. Scandinavian Journal of Clinical and Laboratory Investigation, 26, 327–335.

    Article  PubMed  CAS  Google Scholar 

  • Kanekar, A. (2010). Biomarkers predicting progression of human immunodeficiency virus-related disease. Journal of Clinical Medicine and Research, 2, 55–61.

    CAS  Google Scholar 

  • Krylov, S. N., Arriaga, E. A., Chan, N. W., Dovichi, N. J., & Palcic, M. M. (2000). Metabolic cytometry: Monitoring oligosaccharide biosynthesis in single cells by capillary electrophoresis. Analytical Biochemistry, 283, 133–135.

    Article  PubMed  CAS  Google Scholar 

  • Ladha, J. S., Tripathy, M. K., & Mitra, D. (2005). Mitochondrial complex I activity is impaired during HIV-1-induced T-cell apoptosis. Cell Death and Differentiation, 12, 1417–1428.

    Article  PubMed  CAS  Google Scholar 

  • Larsson, A., Wachtmeister, L., von Wendt, L., Andersson, R., Hagenfeldt, L., & Herrin, K. M. (1985). Ophthalmological, psychometric and therapeutic investigations in two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria). Neuropediatrics, 16, 131–136.

    Article  PubMed  CAS  Google Scholar 

  • Macho, A., Castedo, M., Marchetti, P., et al. (1995). Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers. Blood, 86, 2481–2487.

    PubMed  CAS  Google Scholar 

  • Matias, I., Gonthier, M. P., Petrosino, S., et al. (2007). Role and regulation of acylethanolamides in energy balance: Focus on adipocytes and beta-cells. British Journal of Pharmacology, 152, 676–690.

    Article  PubMed  CAS  Google Scholar 

  • Meyaard, L., Otto, S., Jonker, R., Mijnster, M., Keet, R., & Miedema, F. (1992). Programmed death of T cells in HIV-1 infection. Science, 257, 217–219.

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa, S., & Cuthill, I. C. (2007). Effect size, confidence interval and statistical significance: A practical guide for biologists. Biological Reviews of the Cambridge Philosophical Society, 82, 591–605.

    Article  PubMed  Google Scholar 

  • Nordström, A., & Lewensohn, R. (2010). Metabolomics: Moving to the clinic. Journal of Neuroimmune Pharmacology, 5, 4–17.

    Article  PubMed  Google Scholar 

  • Pendyala, G., & Fox, H. S. (2010). Proteomic and metabolomic strategies to investigate HIV-associated neurocognitive disorders. Genome Medicine, 2, 22.

    Article  PubMed  Google Scholar 

  • Pfaller, M. A., & Diekema, D. J. (2007). Epidemiology of invasive candidiasis: A persistent public health problem. Clinical Microbiology Reviews, 20, 133–163.

    Article  PubMed  CAS  Google Scholar 

  • Philippeos, C., Steffens, F. E., & Meyer, D. (2009). Comparative 1H NMR-based metabonomic analysis of HIV-1 sera. Journal of Biomolecular NMR, 44, 127–137.

    Article  PubMed  CAS  Google Scholar 

  • Pinti, M., Nasi, M., Gibellini, L., et al. (2010). The Role of Mitochondria in HIV Infection and Its Treatment. Journal of Experimental and Clinical Medicine, 2, 145–155.

    Article  CAS  Google Scholar 

  • Pitt, J. J., Eggington, M., & Kahler, S. G. (2002). Comprehensive screening of urine samples for inborn errors of metabolism by electrospray tandem mass spectrometry. Clinical Chemistry, 48, 1970–1980.

    PubMed  CAS  Google Scholar 

  • Psychogios, N., Hau, D. D., Peng, J., et al. (2011). The human serum metabolome. PLoS One, 6, e16957.

    Article  PubMed  CAS  Google Scholar 

  • Redestig, H., Fukushima, A., Stenlund, H., et al. (2009). Compensation for systematic cross-contribution improves normalization of mass spectrometry based metabolomics data. Analytical Chemistry, 81, 7974–7980.

    Article  PubMed  CAS  Google Scholar 

  • Reinecke, C., Koekemoer, G., van der Westhuizen, F. H., et al. (2011). Metabolomics of urinary organic acids in respiratory chain deficiencies in children. Metabolomics. doi:10.1007/s11306-011-0309-0.

  • Ricci, J. E., Munoz-Pinedo, C., Fitzgerald, P., et al. (2004). Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell, 117, 773–786.

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez de Fonseca, F., Navarro, M., Gomez, R., et al. (2001). An anorexic lipid mediator regulated by feeding. Nature, 414, 209–212.

    Article  PubMed  CAS  Google Scholar 

  • Roederer, M. (2001). Spectral compensation for flow cytometry: Visualization artifacts, limitations, and caveats. Cytometry, 45, 194–205.

    Article  PubMed  CAS  Google Scholar 

  • Roshal, M., Zhu, Y., & Planelles, V. (2001). Apoptosis in AIDS. Apoptosis, 6, 103–116.

    Article  PubMed  CAS  Google Scholar 

  • Silva, A. R., Silva, C. G., Ruschel, C., et al. (2001). l-pyroglutamic acid inhibits energy production and lipid synthesis in cerebral cortex of young rats in vitro. Neurochemical Research, 26, 1277–1283.

    Article  PubMed  CAS  Google Scholar 

  • Sreekumar, A., Poisson, L. M., Rajendiran, T. M., et al. (2009). Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature, 457, 910–914.

    Article  PubMed  CAS  Google Scholar 

  • Staal, F. J. T., Ela, S. W., Roederer, M., Anderson, M. T., Herzenberg, L. A., & Herzenberg, L. A. (1992). Glutathione deficiency and human immunodeficiency virus infection. Lancet, 339, 909–912.

    Article  PubMed  CAS  Google Scholar 

  • Sysi-Aho, M., Katajamaa, M., Yetukuri, L., & Oresic, M. (2007). Normalization method for metabolomics data using optimal selection of multiple internal standards. BMC Bioinformatics, 8, 93.

    Article  PubMed  Google Scholar 

  • Touloumi, G., & Hatzakis, A. (2000). Natural history of HIV-1 infection. Clinics in Dermatology, 18, 389–399.

    Article  PubMed  CAS  Google Scholar 

  • Trygg, J., Holmes, E., & Lundstedt, T. (2007). Chemometrics in metabonomics. Journal of Proteome Research, 6, 469–479.

    Article  PubMed  CAS  Google Scholar 

  • Tuck, M. K., Chan, D. W., Chia, D., et al. (2009). Standard operating procedures for serum and plasma collection: Early detection research network consensus statement standard operating procedure integration working group. Journal of Proteome Research, 8, 113–117.

    Article  PubMed  CAS  Google Scholar 

  • Tusher, V. G., Tibshirani, R., & Chu, G. (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Science, 98, 5116–5121.

    Article  CAS  Google Scholar 

  • UNAIDS. (2002). AIDS epidemic update, Geneva, Switzerland. http://data.unaids.org/publications/IRC-pub03/epiupdate2002_en.pdf. Accessed 5 July 2011.

  • UNAIDS. (2009). AIDS epidemic update, Geneva, Switzerland. http://data.unaids.org/pub/report/2009/jc1700_epi_update_2009_en.pdf. Accessed 5 July 2011.

  • van Engeland, M., Nieland, L. J., Ramaekers, F. C., Schutte, B., & Reutelingsperger, C. P. (1998). Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry, 31, 1–9.

    Article  PubMed  Google Scholar 

  • Verde, V., Fogliano, V., Ritieni, A., Maiani, G., Morisco, F., & Caporaso, N. (2002). Use of N,N-dimethyl-p-phenylenediamine to evaluate the oxidative status of human plasma. Free Radical Research, 36, 869–873.

    Article  PubMed  CAS  Google Scholar 

  • Whitmore, C. D., Hindsgaul, O., Palcic, M. M., Schnaar, R. L., & Dovichi, N. J. (2007). Metabolic cytometry. Glycosphingolipid metabolism in single cells. Analytical Chemistry, 79, 5139–5142.

    Article  PubMed  CAS  Google Scholar 

  • Wikoff, W. R., Pendyala, G., Siuzdak, G., & Fox, H. S. (2008). Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques. Journal of Clinical Investigation, 118, 2661–2669.

    Article  PubMed  CAS  Google Scholar 

  • Wohl, D. A., McComsey, G., Tebas, P., et al. (2006). Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clinical Infectious Diseases, 43, 645–653.

    Article  PubMed  CAS  Google Scholar 

  • World Health Organization. (2005). Interim WHO clinical staging of HIV/AIDS and HIV/AIDS case definitions for surveillance—Africa region. http://www.who.int/hiv/pub/guidelines/clinicalstaging/pdf. Accessed 1 July 2011.

  • World health Organization. (2006). Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach, p. 12. http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf. Accessed 1 July 2011.

  • Xu, F., Zou, L., & Ong, C. N. (2009). Multiorigination of chromatographic peaks in derivatized GC/MS metabolomics: A confounder that influences metabolic pathway interpretation. Journal of Proteome Research, 8, 5657–5665.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the following institutions and agencies: the National Research Foundation; Biotechnology Partnerships and Development (BIOPAD, now called the Technology Innovation Agency); the Medical Research Council; the Centre for the Study of AIDS and the Faculty of Science at the University of Pretoria.

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The authors declare no conflict of interest.

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Correspondence to Debra Meyer.

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Williams, A., Koekemoer, G., Lindeque, Z. et al. Qualitative serum organic acid profiles of HIV-infected individuals not on antiretroviral treatment. Metabolomics 8, 804–818 (2012). https://doi.org/10.1007/s11306-011-0376-2

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