European Mitochondrial DNA Haplogroups are Associated with Cerebrospinal Fluid Biomarkers of Inflammation in HIV Infection

David C. Samuels, Asha R. Kallianpur, Ronald J. Ellis, William S. Bush, Scott Letendre, Donald Franklin, Igor Grant, Todd Hulgan

Abstract


Background: Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults.

Methods: CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is a US-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments. Participants who consented to DNA collection underwent whole blood mtDNA sequencing, and a subset also underwent lumbar puncture. IL-6, IL-8, TNF-α (high-sensitivity), and IP-10 were measured in cerebrospinal fluid (CSF) by immunoassay. Multivariable regression of mtDNA haplogroups and log-transformed CSF biomarkers were stratified by genetic ancestry using whole-genome nuclear DNA genotyping (European [EA], African [AA], or Hispanic ancestry [HA]), and adjusted for age, sex, antiretroviral therapy (ART), detectable CSF HIV RNA, and CD4 nadir. A total of 384 participants had both CSF cytokine measures and genetic data (45% EA, 44% AA, 11% HA, 22% female, median age 43 years, 74% on ART).

Results: In analyses stratified by the 3 continental ancestry groups, no haplogroups were significantly associated with the 4 biomarkers. In the subgroup of participants with undetectable plasma HIV RNA on ART, European haplogroup H participants had significantly lower CSF TNF-α (P = 0.001).
Conclusions: Lower CSF TNF-α may indicate lower neuroinflammation in the haplogroup H participants with well-controlled HIV on ART.


Full Text:

HTML PDF

References


1. Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, Fundel-Clemens K, Zondler L, Brenner D, Martin-Villalba A, Hengerer B, Kassubek J, Ludolph AC, Weishaupt JH, Danzer KM. Inflammatory dysregulation of blood monocytes in Parkinson's disease patients. Acta Neuropathologica. 2014;128(5):651-63. PubMed PMID: WOS:000344058200004. doi: 10.1007/s00401-014-1345-4

2. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001;410(6831):988-94. PubMed PMID: WOS:000168152300059. doi: 10.1038/35073667

3. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178-201. PubMed PMID: WOS:000252758400004. doi: 10.1016/j.neuron.2008.01.003

4. Burdo TH, Lackner A, Williams KC. Monocyte/macrophages and their role in HIV neuropathogenesis. Immunological Reviews. 2013;254:102-13. PubMed PMID: WOS:000320390900007. doi: 10.1111/imr.12068

5. Zayyad Z, Spudich S. Neuropathogenesis of HIV: From Initial Neuroinvasion to HIV-Associated Neurocognitive Disorder (HAND). Current Hiv/Aids Reports. 2015;12(1):16-24. PubMed PMID: WOS:000351307700003. doi: 10.1007/s11904-014-0255-3

6. McGuire JL, Gill AJ, Douglas SD, Kolson DL, Cns HIVA-RTE. Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. Journal of Neurovirology. 2015;21(4):439-48. PubMed PMID: WOS:000358336100011. doi: 10.1007/s13365-015-0333-3

7. Ellis R. HIV and antiretroviral therapy: Impact on the central nervous system. Progress in Neurobiology. 2010;91(2):185-7. PubMed PMID: WOS:000278238600010. doi: 10.1016/j.pneurobio.2009.10.016

8. Heaton RK, Franklin DR, Jr., Deutsch R, Letendre S, Ellis RJ, Casaletto K, Marquine MJ, Woods SP, Vaida F, Atkinson JH, Marcotte TD, McCutchan JA, Collier AC, Marra CM, Clifford DB, Gelman BB, Sacktor N, Morgello S, Simpson DM, Abramson I, Gamst AC, Fennema-Notestine C, Smith DM, Grant I, Grp C. Neurocognitive Change in the Era of HIV Combination Antiretroviral Therapy: The Longitudinal CHARTER Study. Clinical Infectious Diseases. 2015;60(3):473-80. PubMed PMID: WOS:000349761600028. doi: 10.1093/cid/ciu862

9. Kallianpur AR, Levine AJ. Host Genetic Factors Predisposing to HIV-Associated Neurocognitive Disorder. Current Hiv/Aids Reports. 2014;11(3):336-52. PubMed PMID: WOS:000340368500015. doi: 10.1007/s11904-014-0222-z

10. Letendre SL, Lanier ER, McCutchan JA. Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1. Journal of Infectious Diseases. 1999;180(2):310-9. PubMed PMID: WOS:000081767000009. doi: 10.1086/314866

11. Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, Young AC, Walter R, Fuchs D, Brew BJ, Cinque P, Robertson K, Hagberg L, Zetterberg H, Gisslen M, Spudich S. Cerebrospinal Fluid and Neuroimaging Biomarker Abnormalities Suggest Early Neurological Injury in a Subset of Individuals During Primary HIV Infection. Journal of Infectious Diseases. 2013;207(11):1703-12. PubMed PMID: WOS:000318563200011. doi: 10.1093/infdis/jit088

12. Brew BJ, Bhalla RB, Paul M, Sidtis JJ, Kelip JJ, Sadler AE, Gallardo H, McArthur JC, Schwartz MK, Price RW. Cerebrospinal-fluid beta-2-microglobulin in patients with AIDS dementia complex - an expanded series including response to Zidovudine treatment. Aids. 1992;6(5):461-5. PubMed PMID: WOS:A1992HT19700004. 10.1097/00002030-199205000-00004

13. Brew BJ, Dunbar N, Pemberton L, Kaldor J. Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta(2),-microglobulin and neopterin. Journal of Infectious Diseases. 1996;174(2):294-8. PubMed PMID: WOS:A1996UZ09300008.

14. Fuchs D, Chiodi F, Albert J, Asjo B, Hagberg L, Hausen A, Norkrans G, Reibnegger G, Werner ER, Wachter H. Neopterin concentrations in cerebrospinal-fluid and serum of individuals infected with HIV-1. Aids. 1989;3(5):285-8. PubMed PMID: WOS:A1989U853000006. doi: 10.1097/00002030-198905000-00006

15. Hagberg L, Dotevall L, Norkrans G, Larsson M, Wachter H, Fuchs D. Cerebrospinal-fluid neopterin concentrations in central-nervous-system infection. Journal of Infectious Diseases. 1993;168(5):1285-8. PubMed PMID: WOS:A1993MC89000033.

16. Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K. Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology. 2004;63(11):2084-90. PubMed PMID: WOS:000225711400019.

17. Vullo V, Mastroianni CM, Lichtner M, Mengoni F, Delia S. Increased cerebrospinal-fluid levels of soluble receptors for tumor-necrosis-factor in HIV-infected patients with neurological diseases. Aids. 1995;9(9):1099-100. PubMed PMID: WOS:A1995RU01300018.

18. Woods SP, Morgan EE, Marquie-Beck J, Carey CL, Grant I, Letendre SL, Center HIVNR. Markers of macrophage activation and axonal injury are associated with prospective memory in HIV-1 disease. Cognitive and Behavioral Neurology. 2006;19(4):217-21. PubMed PMID: WOS:000243054900009. 10.1097/01.wnn.0000213916.10514.57

19. Letendre SL, Zheng JC, Kaul M, Yiannoutsos CT, Ellis RJ, Taylor MJ, Marquie-Beck J, Navia B, Consortium HIVN. Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals. Journal of Neurovirology. 2011;17(1):63-9. PubMed PMID: WOS:000289580200008. doi: 10.1007/s13365-010-0013-2

20. Brosseron F, Krauthausen M, Kummer M, Heneka MT. Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer's Disease: a Comparative Overview. Molecular Neurobiology. 2014;50(2):534-44. PubMed PMID: WOS:000343157900022. doi: 10.1007/s12035-014-8657-1

21. Kramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes:, Implications for their use as bioenergetic biomarkers. Redox Biology. 2014;2:206-10. PubMed PMID: WOS:000350769600026.

22. Hart AB, Samuels DC, Hulgan T. The Other Genome: A Systematic Review of Studies of Mitochondrial DNA Haplogroups and Outcomes of HIV Infection and Antiretroviral Therapy. Aids Reviews. 2013;15(4):213-20. PubMed PMID: WOS:000343365300003.

23. Bellizzi D, Cavalcante P, Taverna D, Rose G, Passarino G, Salvioli S, Franceschi C, De Benedictis G. Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines. Genes to Cells. 2006;11(8):883-91. PubMed PMID: WOS:000239162300004. doi: 10.1111/j.1365-2443.2006.00986.x

24. Kenney MC, Chwa M, Atilano SR, Falatoonzadeh P, Ramirez C, Malik D, Tarek M, Caceres-del-Carpio J, Nesburn AB, Boyer DS, Kuppermann BD, Vawter M, Jazwinski SM, Miceli M, Wallace DC, Udar N. Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions. Human Molecular Genetics. 2014;23(13):3537-51. PubMed PMID: WOS:000338126300016. doi: 10.1093/hmg/ddu065

25. Atilano SR, Malik D, Chwa M, Caceres-Del-Carpio J, Nesburn AB, Boyer DS, Kuppermann BD, Jazwinski SM, Miceli MV, Wallace DC, Udar N, Kenney MC. Mitochondrial DNA variants can mediate methylation status of inflammation, angiogenesis and signaling genes. Human Molecular Genetics. 2015;24(16):4491-503. PubMed PMID: WOS:000361315400002. doi: 10.1093/hmg/ddv173

26. Hulgan T, Samuels DC, Bush W, Ellis RJ, Letendre SL, Heaton RK, Franklin DR, Straub P, Murdock DG, Clifford DB, Collier AC, Gelman BB, Marra CM, McArthur JC, McCutchan JA, Morgello S, Simpson DM, Grant I, Kallianpur AR. Mitochondrial DNA Haplogroups and Neurocognitive Impairment during HIV Infection. Clinical Infectious Diseases. 2015;61:1476-84.

27. Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nature Reviews Neuroscience. 2007;8(1):33-44. PubMed PMID: WOS:000242994200014. doi: 10.1038/nrn2040

28. Price RW, Epstein LG, Becker JT, Cinque P, Gisslen M, Pulliam L, McArthur JC. Biomarkers of HIV-1CNS infection and injury. Neurology. 2007;69(18):1781-8. PubMed PMID: WOS:000250518100008. doi: 10.1212/01.wnl.0000278457.55877.eb

29. Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Grp C. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy CHARTER Study. Neurology. 2010;75(23):2087-96. PubMed PMID: WOS:000285044300011. doi: 10.1212/WNL.0b013e318200d727

30. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-99. PubMed PMID: WOS:000250518100009. doi: 10.1212/01.WNL.0000287431.88658.8b

31. Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, LeBlanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Charter, Grp H. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. Journal of Neurovirology. 2011;17(1):3-16. PubMed PMID: WOS:000289580200002. doi: 10.1007/s13365-010-0006-1

32. Xie HBM, Perin JC, Schurr TG, Dulik MC, Zhadanov SI, Baur JA, King MP, Place E, Clarke C, Grauer M, Schug J, Santani A, Albano A, Kim C, Procaccio V, Hakonarson H, Gai XW, Falk MJ. Mitochondrial genome sequence analysis: A custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy. Bmc Bioinformatics. 2011;12. PubMed PMID: WOS:000297784600001.402. doi: 10.1186/1471-2105-12-402

33. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet. 1999;23(2):147. PubMed PMID: 10508508. doi: 10.1038/13779

34. Kloss-Brandstatter A, Pacher D, Schonherr S, Weissensteiner H, Binna R, Specht G, Kronenberg F. HaploGrep: A Fast and Reliable Algorithm for Automatic Classification of Mitochondrial DNA Haplogroups. Human Mutation. 2011;32(1):25-32. PubMed PMID: WOS:000286281800011. doi: 10.1002/humu.21382

35. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics. 2006;38(8):904-9. PubMed PMID: WOS:000239325700019. doi: 10.1038/ng1847

36. Mitchell SL, Goodloe R, Brown-Gentry K, Pendergrass SA, Murdock DG, Crawford DC. Characterization of mitochondrial haplogroups in a large population-based sample from the United States. Human Genetics. 2014;133(7):861-8. PubMed PMID: WOS:000337088600003. doi: 10.1007/s00439-014-1421-9

37. Pereira L, Soares P, Radivojac P, Li BA, Samuels DC. Comparing Phylogeny and the Predicted Pathogenicity of Protein Variations Reveals Equal Purifying Selection across the Global Human mtDNA Diversity. American Journal of Human Genetics. 2011;88(4):433-9. PubMed PMID: WOS:000289664300003. doi: 10.1016/j.ajhg.2011.03.006

38. Gomez-Duran A, Pacheu-Grau D, Lopez-Gallardo E, Diez-Sanchez C, Montoya J, Lopez-Perez MJ, Ruiz-Pesini E. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Human Molecular Genetics. 2010;19(17):3343-53. PubMed PMID: WOS:000280704800005. doi: 10.1093/hmg/ddq246

39. Herrnstadt C, Howell N. An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders. Mitochondrion. 2004;4(5-6):791-8. PubMed PMID: WOS:000226172600038. doi: 10.1016/j.mito.2004.07.041

40. Raule N, Sevini F, Santoro A, Altilia S, Franceschi C. Association studies on human mitochondrial DNA: Methodological aspects and results in the most common age-related diseases. Mitochondrion. 2007;7(1-2):29-38. PubMed PMID: WOS:000245701400006. doi: 10.1016/j.mito.2006.11.013

41. Hendrickson SL, Hutcheson HB, Ruiz-Pesini E, Poole JC, Lautenberger J, Sezgin E, Kingsley L, Goedert JJ, Vlahov D, Donfield S, Wallace DC, O'Brien SJ. Mitochondrial DNA haplogroups influence AIDS progression. Aids. 2008;22(18):2429-39. PubMed PMID: WOS:000261772300003. doi: 10.1097/QAD.0b013e32831940bb

42. Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, Fauci AS. Tumor Necrosis Factor-Alpha Induces Expression of Human Immunodeficiency Virus in a Chronically Infected T-Cell Clone. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(7):2365-8. PubMed PMID: WOS:A1989U042300051. doi: 10.1073/pnas.86.7.2365

43. Mellors JW, Griffith BP, Ortiz MA, Landry ML, Ryan JL. Tumor-Necrosis-Factor-Alpha Cachectin Enhances Human-Immunodeficiency-Virus Type-1 Replication in Primary Macrophages. Journal of Infectious Diseases. 1991;163(1):78-82. PubMed PMID: WOS:A1991EP67800014.

44. Poli G, Kinter A, Justement JS, Kehrl JH, Bressler P, Stanley S, Fauci AS. Tumor Necrosis Factor-Alpha Functions in an Autocrine Manner in the Induction of Human Immunodeficiency Virus Expression. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(2):782-5. PubMed PMID: WOS:A1990CK37800058. doi: 10.1073/pnas.87.2.782

45. Errea O, Moreno B, Gonzalez-Franquesa A, Garcia-Roves PM, Villoslada P. The disruption of mitochondrial axonal transport is an early event in neuroinflammation. Journal of Neuroinflammation. 2015;12. PubMed PMID: WOS:000360116700001.152. doi: 10.1186/s12974-015-0375-8

46. Trudler D, Nash Y, Frenkel D. New insights on Parkinson's disease genes: the link between mitochondria impairment and neuroinflammation. Journal of Neural Transmission. 2015;122(10):1409-19. PubMed PMID: WOS:000363273700007. doi: 10.1007/s00702-015-1399-z

47. Verri M, Pastoris O, Dossena M, Aquilani R, Guerriero F, Cuzzoni G, Venturini L, Ricevuti G, Bongiorno AI. MITOCHONDRIAL ALTERATIONS, OXIDATIVE STRESS AND NEUROINFLAMMATION IN ALZHEIMER'S DISEASE. International Journal of Immunopathology and Pharmacology. 2012;25(2):345-53. PubMed PMID: WOS:000305879500004.

48. Witte ME, Geurts JJG, de Vries HE, van der Valk P, van Horssen J. Mitochondrial dysfunction: A potential link between neuroinflammation and neurodegeneration? Mitochondrion. 2010;10(5):411-8. PubMed PMID: WOS:000281051500002. doi: 10.1016/j.mito.2010.05.014

49. Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, Gabuzda D. Monocyte Activation Markers in Cerebrospinal Fluid Associated With Impaired Neurocognitive Testing in Advanced HIV Infection. Jaids-Journal of Acquired Immune Deficiency Syndromes. 2012;60(3):234-43. PubMed PMID: WOS:000305804400013. doi: 10.1097/QAI.0b013e318256f3bc

50. Marcotte TD, Deutsch R, Michael BD, Franklin D, Cookson DR, Bharti AR, Grant I, Letendre SL, Grp C. A Concise Panel of Biomarkers Identifies Neurocognitive Functioning Changes in HIV-Infected Individuals. Journal of Neuroimmune Pharmacology. 2013;8(5):1123-35. PubMed PMID: WOS:000328496000011. doi: 10.1007/s11481-013-9504-2

51. Larsen S, Diez-Sanchez C, Rabol R, Ara I, Dela F, Helge JW. Increased intrinsic mitochondrial function in humans with mitochondrial haplogroup H. Biochimica Et Biophysica Acta-Bioenergetics. 2014;1837(2):226-31. PubMed PMID: WOS:000330498700002. doi: 10.1016/j.bbabio.2013.10.009

52. Mueller EE, Brunner SM, Mayr JA, Stanger O, Sperl W, Kofler B. Functional Differences between Mitochondrial Haplogroup T and Haplogroup H in HEK293 Cybrid Cells. Plos One. 2012;7(12). PubMed PMID: WOS:000313618800073.e52367. doi: 10.1371/journal.pone.0052367

53. Bulstrode H, Nicoll JAR, Hudson G, Chinnery PF, Di Pietro V, Belli A. Mitochondrial DNA and traumatic brain injury. Annals of Neurology. 2014;75(2):186-95. PubMed PMID: WOS:000333005000006. doi: 10.1002/ana.24116

54. Tranah GJ, Nalls MA, Katzman SM, Yokoyama JS, Lam ET, Zhao Y, Mooney S, Thomas F, Newman AB, Liu Y, Cummings SR, Harris TB, Yaffe K, Hlth A, Body Composition S. Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly. Journal of Alzheimers Disease. 2012;32(2):357-72. PubMed PMID: WOS:000309977800010. doi: 10.3233/jad-2012-120466


Article Level Metrics

Refbacks

  • There are currently no refbacks.




Copyright (c) 2017 David C. Samuels

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

© Pathogens and Immunity 2017