Purinergic Signalling

, Volume 14, Issue 4, pp 309–320 | Cite as

Adenosine signaling and adenosine deaminase regulation of immune responses: impact on the immunopathogenesis of HIV infection

  • Daniela F. Passos
  • Viviane M. Bernardes
  • Jean L. G. da Silva
  • Maria R. C. Schetinger
  • Daniela Bitencourt Rosa LealEmail author
Review Article


Infection by human immunodeficiency virus (HIV) causes the acquired immune deficiency syndrome (AIDS), which has devastating effects on the host immune system. HIV entry into host cells and subsequent viral replication induce a proinflammatory response, hyperactivating immune cells and leading them to death, disfunction, and exhaustion. Adenosine is an immunomodulatory molecule that suppresses immune cell function to protect tissue integrity. The anti-inflammatory properties of adenosine modulate the chronic inflammation and immune activation caused by HIV. Lack of adenosine contributes to pathogenic events in HIV infection. However, immunosuppression by adenosine has its shortcomings, such as impairing the immune response, hindering the elimination of the virus and control of viral replication. By attempting to control inflammation, adenosine feeds a pathogenic cycle affecting immune cells. Deamination of adenosine by ADA (adenosine deaminase) counteracts the negative effects of adenosine in immune cells, boosting the immune response. This review comprises the connection between adenosinergic system and HIV immunopathogenesis, exploring defects in immune cell function and the role of ADA in protecting these cells against damage.


HIV infection Adenosine Adenosine deaminase Inflammation 



Programa de Bolsas de Iniciação Científica do Hospital Universitário de Santa Maria (PROIC/UFSM), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Compliance with ethical standards

Conflicts of interest

Daniela F. Passos declares that she has no conflict of interest.

Viviane M. Bernardes declares that she has no conflict of interest.

Jean L. G. da Silva declares that she has no conflict of interest.

Maria R. C. Schetinger declares that she has no conflict of interest.

Daniela B. R. Leal declares that she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Yegutkin GG (2008) Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochim Biophys Acta-Mol Cell Res 1783:673–694. CrossRefGoogle Scholar
  2. 2.
    Bours MJL, Swennen ELR, Di Virgilio F et al (2006) Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther 112:358–404. CrossRefPubMedGoogle Scholar
  3. 3.
    Ohta A (2016) A metabolic immune checkpoint: adenosine in tumor microenvironment. Front Immunol 7:109. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Vijayan D, Young A, Teng MWL, Smyth MJ (2017) Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer 17(12):709–724. CrossRefPubMedGoogle Scholar
  5. 5.
    Drygiannakis I, Ernst PB, Lowe D, Glomski IJ (2011) Immunological alterations mediated by adenosine during host-microbial interactions. Immunol Res 50(1):69–77. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ciruela F, Saura C, Canela EI, Mallol J, Lluis C, Franco R (1996) Adenosine deaminase affects ligand-induced signalling by interacting with cell surface adenosine receptors. FEBS Lett 380:219–223. CrossRefPubMedGoogle Scholar
  7. 7.
    Deeks SG (2013) HIV infection, inflammation, immunosenescence, and aging. Ann Rev Med 62:141–155. CrossRefGoogle Scholar
  8. 8.
    Deeks SG, Tracy R, Douek DC (2013) Systemic effects of inflammation on health during chronic HIV infection. Immunity 39:633–645. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ohta A, Sitkovsky M (2014) Extracellular adenosine-mediated modulation of regulatory T cells. Front Immunol 5:1–9. CrossRefGoogle Scholar
  10. 10.
    Newby AC (1984) Adenosine and the concept of “retaliatory metabolites”. Trends Biochem Sci 9:42–44. CrossRefGoogle Scholar
  11. 11.
    Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G (2010) Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol 88(2):279–290. CrossRefPubMedGoogle Scholar
  12. 12.
    Kumar V, Sharma A (2009) Adenosine: an endogenous modulator of innate immune system with therapeutic potential. Eur J Pharmacol 616:7–15. CrossRefPubMedGoogle Scholar
  13. 13.
    Sitkovsky MV, Ohta A (2005) The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol 26:299–304. CrossRefPubMedGoogle Scholar
  14. 14.
    Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920. CrossRefPubMedGoogle Scholar
  15. 15.
    Liang D, Zuo A, Shao H, Chen M, Kaplan HJ, Sun D (2014) The anti- or pro-inflammatory effect of an adenosine receptor agonist on the Th17 autoimmune response is inflammatory environmental-dependent. J Immunol 193:5498–5505. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sciaraffia E, Riccomi A, Lindstedt R, Gesa V, Cirelli E, Patrizio M, de Magistris MT, Vendetti S (2014) Human monocytes respond to extracellular cAMP through A2A and A2B adenosine receptors. J Leukoc Biol 96:113–122. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Arumugham VB, Baldari CT (2017) cAMP: a multifaceted modulator of immune synapse assembly and T cell activation. J Leukoc Biol 101(6):1301–1316. CrossRefPubMedGoogle Scholar
  18. 18.
    Schuler PJ, Macatangay BJC, Saze Z, Jackson EK, Riddler SA, Buchanan WG, Hilldorfer BB, Mellors JW, Whiteside TL, Rinaldo CR (2013) CD4(+)CD73(+) T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression. AIDS 27:1545–1555. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Haskó G, Kuhel DG, Chen J, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabó C (2000) Adenosine inhibits IL-12 and TNF-α production via adenosine A 2a receptor-dependent and independent mechanisms. FASEB J 14:2065–2074. CrossRefPubMedGoogle Scholar
  20. 20.
    Panther E, Corinti S, Idzko M, Herouy Y, Napp M, la Sala A, Girolomoni G, Norgauer J (2003) Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101:3985–3990. CrossRefPubMedGoogle Scholar
  21. 21.
    Cadogan M, Dalgleish AG (2017) HIV immunopathogenesis and strategies for intervention. Lancet Infect Dis 8:675–684. CrossRefGoogle Scholar
  22. 22.
    Swanstrom R, Coffin J (2012) HIV-1 Pathogenesis: the virus. Cold Spring Harb Perspect Med 2(12):a007443. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mogensen TH, Melchjorsen J, Larsen CS, Paludan SR (2010) Innate immune recognition and activation during HIV infection. Retrovirology 7:54. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Altfeld M, Gale M (2015) Innate immunity against HIV-1 infection. Nat Immunol 16:554–562. CrossRefGoogle Scholar
  25. 25.
    Altfeld M, Fadda L, Frleta D, Bhardwaj N (2011) DCs and NK cells: critical effectors in the immune response to HIV-1. Nat Rev Immunol 11:176–186. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Aggarwal A, McAllery S, Turville SG (2013) Revising the role of myeloid cells in HIV pathogenesis. Curr HIV/AIDS Rep 10:3–11. CrossRefPubMedGoogle Scholar
  27. 27.
    Rustagi A, Gale M (2014) Innate antiviral immune signaling, viral evasion and modulation by HIV-1. J Mol Biol 426:1161–1177. CrossRefPubMedGoogle Scholar
  28. 28.
    Bowers NL, Helton ES, Huijbregts RPH, Goepfert PA, Heath SL, Hel Z (2014) Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathog 10(3):e1003993. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mehraj V, Jenabian M, Vyboh K, Routy J (2014) Immune suppression by myeloid cells in HIV infection: new targets for immunotherapy. Open AIDS J 29(8):66–78. CrossRefGoogle Scholar
  30. 30.
    Walker B, McMichael A (2012) The T-cell response to HIV. Cold Spring Harb Perspect Med 2(11).
  31. 31.
    Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA (2002) HIV preferentially infects HIV-specific CD4+ T cells. Nature 417:95–98. CrossRefPubMedGoogle Scholar
  32. 32.
    Carter CA, Ehrlich LS (2008) Cell biology of HIV-1 infection of macrophages. Annu Rev Microbiol 62:425–443. CrossRefPubMedGoogle Scholar
  33. 33.
    Burleigh L, Lozach P-Y, Schiffer C, Staropoli I, Pezo V, Porrot F, Canque B, Virelizier JL, Arenzana-Seisdedos F, Amara A (2006) Infection of dendritic cells (DCs), not DC-SIGN-mediated internalization of human immunodeficiency virus, is required for long-term transfer of virus to T cells. J Virol 80:2949–2957. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cao W, Mehraj V, Kaufmann DE, Li T, Routy JP (2016) Elevation and persistence of CD8 T-cells in HIV infection: the Achilles heel in the ART era. J Int AIDS Soc 19(1):20697. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kumar A, Abbas W, Herbein G (2014) HIV-1 latency in monocytes/macrophages. Viruses 6:1837–1860. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kedzierska K, Crowe SM (2002) The role of monocytes and macrophages in the pathogenesis of HIV-1 infection. Curr Med Chem 9(21):1893–1903. CrossRefPubMedGoogle Scholar
  37. 37.
    Moir S, Fauci AS (2009) B cells in HIV infection and disease. Nat Rev Immunol 9:235–245. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Casulli S, Elbim C (2014) Interactions between human immunodeficiency virus type 1 and polymorphonuclear neutrophils. J Innate Immun 6:13–20. CrossRefPubMedGoogle Scholar
  39. 39.
    Brunetta E, Hudspeth KL, Mavilio D (2010) Pathologic natural killer cell subset redistribution in HIV-1 infection: new insights in pathophysiology and clinical outcomes. J Leukoc Biol 88:1119–1130. CrossRefPubMedGoogle Scholar
  40. 40.
    Torre D, Pugliese A (2008) Platelets and HIV-1 infection: old and new aspects. Curr HIV Res 6:411–418. CrossRefPubMedGoogle Scholar
  41. 41.
    Appay V, Sauce D (2008) Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 214:231–241. CrossRefPubMedGoogle Scholar
  42. 42.
    Klatt NR, Funderburg NT, Brenchley JM (2013) Microbial translocation, immune activation and HIV disease. Trends Microbiol 21:6–13. CrossRefPubMedGoogle Scholar
  43. 43.
    Séror C, Melki M-T, Subra F, Raza SQ, Bras M, Saïdi H, Nardacci R, Voisin L, Paoletti A, Law F, Martins I, Amendola A, Abdul-Sater AA, Ciccosanti F, Delelis O, Niedergang F, Thierry S, Said-Sadier N, Lamaze C, Métivier D, Estaquier J, Fimia GM, Falasca L, Casetti R, Modjtahedi N, Kanellopoulos J, Mouscadet JF, Ojcius DM, Piacentini M, Gougeon ML, Kroemer G, Perfettini JL (2011) Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J Exp Med 208:1823–1834. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hazleton JE, Berman JW, Eugenin EA (2012) Purinergic receptors are required for HIV-1 infection of primary human macrophages. J Immunol 188:4488–4495. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Orellana JA, Velasquez S, Williams DW, Sáez JC, Berman JW, Eugenin EA (2013) Pannexin1 hemichannels are critical for HIV infection of human primary CD4(+) T lymphocytes. J Leukoc Biol 94:399–407. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Jacob F, Novo CP, Bachert C, Van Crombruggen K (2013) Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal 9:285–306. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gombault A, Baron L, Couillin I (2012) ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol 3:414. CrossRefPubMedGoogle Scholar
  48. 48.
    Doitsh G, Galloway NLK, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC (2014) Pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505:509–514. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Nikolova M, Carriere M, Jenabian MA, Limou S, Younas M, Kök A, Huë S, Seddiki N, Hulin A, Delaneau O, Schuitemaker H, Herbeck JT, Mullins JI, Muhtarova M, Bensussan A, Zagury JF, Lelievre JD, Lévy Y (2011) CD39/adenosine pathway is involved in AIDS progression. PLoS Pathog 7(7):e1002110. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Leal DB, Streher CA, Bertoncheli Cde M et al (2005) HIV infection is associated with increased NTPDase activity that correlates with CD39-positive lymphocytes. Biochim Biophys Acta 1746:129–134. CrossRefPubMedGoogle Scholar
  51. 51.
    Schuler PJ, Saze Z, Hong CS, Muller L, Gillespie DG, Cheng D, Harasymczuk M, Mandapathil M, Lang S, Jackson EK, Whiteside TL (2014) Human CD4+CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin Exp Immunol 177:531–543. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Tóth I, Le AQ, Hartjen P et al (2013) Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. J Leukoc Biol 94:551–561. CrossRefPubMedGoogle Scholar
  53. 53.
    He T, Brocca-Cofano E, Gillespie DG, Xu C, Stock JL, Ma D, Policicchio BB, Raehtz KD, Rinaldo CR, Apetrei C, Jackson EK, Macatangay BJC, Pandrea I (2015) Critical role for the adenosine pathway in controlling simian immunodeficiency virus-related immune activation and inflammation in gut mucosal tissues. J Virol 89:9616–9630. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ernst PB, Garrison JC, Thompson LF (2010) Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol 185:1993–1998. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, Nizet V, Insel PA, Junger WG (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314(5806):1792–1795. CrossRefPubMedGoogle Scholar
  56. 56.
    Junger WG (2008) Purinergic regulation of neutrophil chemotaxis. Cell Mol Life Sci 65(16):2528–2540. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kronlage M, Song J, Sorokin L, Isfort K, Schwerdtle T, Leipziger J, Robaye B, Conley PB, Kim HC, Sargin S, Schon P, Schwab A, Hanley PJ (2010) Autocrine purinergic receptor signaling is essential for macrophage Chemotaxis. Sci Signal 3(132):ra55. CrossRefPubMedGoogle Scholar
  58. 58.
    Barletta KE, Ley K, Mehrad B (2012) Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol 32(4):856–864. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Giraldo DM, Hernandez JC, Velilla P, Urcuqui-Inchima S (2015) HIV-1—neutrophil interactions trigger neutrophil activation and Toll-like receptor expression. Immunol Res 64(1):93–103. CrossRefGoogle Scholar
  60. 60.
    Saitoh T, Komano J, Saitoh Y, Misawa T, Takahama M, Kozaki T, Uehata T, Iwasaki H, Omori H, Yamaoka S, Yamamoto N, Akira S (2017) Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe 12:109–116. CrossRefGoogle Scholar
  61. 61.
    Haskó G, Csóka B, Németh ZH, Vizi ES, Pacher P (2009) A(2B) adenosine receptors in immunity and inflammation. Trends Immunol 30:263–270. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Azzam R, Kedzierska K, Leeansyah E, Chan H, Doischer D, Gorry PR, Cunningham AL, Crowe SM, Jaworowski A (2006) Impaired complement-mediated phagocytosis by HIV type-1-infected human monocyte-derived macrophages involves a cAMP-dependent mechanism. AIDS Res Hum Retrovir 22:619–629. CrossRefPubMedGoogle Scholar
  63. 63.
    Chowdhury MIH, Koyanagi Y, Horiuchi S, Hazeki O, Ui M, Kitano K, Golde DW, Takada K, Yamamoto N (1993) cAMP stimulates human immunodeficiency virus (HIV-1)from latently infected cells of monocyte-macrophage lineage: synergism with TNF-α. Virology 194:345–349. CrossRefPubMedGoogle Scholar
  64. 64.
    Fuentes E, Pereira J, Mezzano D, Alarcón M, Caballero J, Palomo I (2014) Inhibition of platelet activation and thrombus formation by adenosine and inosine: studies on their relative contribution and molecular modeling. PLoS One 9(11):e112741. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Graziano F, Desdouits M, Garzetti L, Podini P, Alfano M, Rubartelli A, Furlan R, Benaroch P, Poli G (2015) Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages. Proc Natl Acad Sci 112:E3265–E3273. CrossRefPubMedGoogle Scholar
  66. 66.
    Leslie M (2010) Beyond clotting: the powers of platelets. Science 328(5978):562–564. CrossRefPubMedGoogle Scholar
  67. 67.
    Tsegaye TS, Gnirß K, Rahe-Meyer N et al (2013) Platelet activation suppresses HIV-1 infection of T cells. Retrovirology 10:48. CrossRefGoogle Scholar
  68. 68.
    Beck Z, Jagodzinski LL, Eller MA, Thelian D, Matyas GR, Kunz AN, Alving CR (2013) Platelets and erythrocyte-bound platelets bind infectious HIV-1 in plasma of chronically infected patients. PLoS One 8(11):e81002. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Johnston-Cox HA, Ravid K (2011) Adenosine and blood platelets. Purinergic Signal 7:357–365. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Morrell CN, Aggrey AA, Chapman LM, Modjeski KL (2014) Emerging roles for platelets as immune and inflammatory cells. Blood 123:2759–2767. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Rezer JFP, Souza VCG, Thorstenberg MLP, Ruchel JB, Bertoldo TMD, Zanini D, Silveira KL, Leal CAM, Passos DF, Gonçalves JF, Abdalla FH, Schetinger MRC, Leal DBR (2016) Effect of antiretroviral therapy in thromboregulation through the hydrolysis of adenine nucleotides in platelets of HIV patients. Biomed Pharmacother 79:321–328. CrossRefPubMedGoogle Scholar
  72. 72.
    Rezer JFP, Adefegha SA, Ecker A, Passos DF, Saccol RSP, Bertoldo TMD, Leal DBR (2018) Changes in inflammatory/cardiac markers of HIV positive patients. Microb Pathog 114:264–268. CrossRefPubMedGoogle Scholar
  73. 73.
    Schnurr M, Toy T, Shin A, Hartmann G, Rothenfusser S, Soellner J, Davis ID, Cebon J, Maraskovsky E (2004) Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood 103(4):1391–1397. CrossRefPubMedGoogle Scholar
  74. 74.
    Moreno-Fernandez ME, Rueda CM, Velilla PA, Rugeles MT, Chougnet CA (2012) cAMP during HIV infection: friend or foe? AIDS Res Hum Retrovir 28:49–53. CrossRefPubMedGoogle Scholar
  75. 75.
    Panther E, Idzko M, Herouy Y et al (2001) Expression and function of adenosine receptors in human dendritic cells. FASEB J 15:1963–1970. CrossRefPubMedGoogle Scholar
  76. 76.
    Novitskiy SV, Ryzhov S, Zaynagetdinov R et al (2008) Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112:1822–1831. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Kottilil S, Shin K, Jackson JO, Reitano KN, O'Shea MA, Yang J, Hallahan CW, Lempicki R, Arthos J, Fauci AS (2006) Innate immune dysfunction in HIV infection: effect of HIV envelope-NK cell interactions. J Immunol 176:1107–1114. CrossRefPubMedGoogle Scholar
  78. 78.
    Vignali DAA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Publ Gr 10(7):490–500. CrossRefGoogle Scholar
  80. 80.
    Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR (2006) T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol 177:6780–6786. CrossRefPubMedGoogle Scholar
  81. 81.
    Sitkovsky M, Lukashev D, Deaglio S, Dwyer K, Robson SC, Ohta A (2008) Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells. Br J Pharmacol 153:457–464. CrossRefGoogle Scholar
  82. 82.
    Bopp T, Dehzad N, Reuter S, Klein M, Ullrich N, Stassen M, Schild H, Buhl R, Schmitt E, Taube C (2009) Inhibition of cAMP degradation improves regulatory T cell-mediated suppression. J Immunol 182:4017–4024. CrossRefPubMedGoogle Scholar
  83. 83.
    Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Parish ST, Kim S, Sekhon RK, Wu JE, Kawakatsu Y, Effros RB (2010) Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes. Immunol 184:2847–2854. CrossRefGoogle Scholar
  85. 85.
    Maini MK, Soares MV, Zilch CF et al (1999) Virus-induced CD8+ T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence. J Immunol 162(8):4521–4526. CrossRefPubMedGoogle Scholar
  86. 86.
    Chou JP, Ramirez CM, Wu JE, Effros RB (2013) Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8+ T cells. PLoS One 8(5):e64702. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Ohta A, Ohta A, Madasu M, Kini R, Subramanian M, Goel N, Sitkovsky M (2009) A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 183:5487–5493. CrossRefPubMedGoogle Scholar
  88. 88.
    Koshiba M, Rosin DL, Hayashi N, Linden J, Sitkovsky MV (1999) Patterns of A2A extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A2A receptor monoclonal antibodies. Mol Pharmacol 55:614–624PubMedGoogle Scholar
  89. 89.
    Gessi S, Varani K, Merighi S, Fogli E, Sacchetto V, Benini A, Leung E, Mac-Lennan S, Borea PA (2007) Adenosine and lymphocyte regulation. Purinergic Signal 3:109–116. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Linden J, Cekic C (2012) Regulation of lymphocyte function by adenosine. Arterioscler Thromb Vasc Biol 32:2097–2103. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Jenabian MA, Seddiki N, Yatim A, Carriere M, Hulin A, Younas M, Ghadimi E, Kök A, Routy JP, Tremblay A, Sévigny J, Lelievre JD, Levy Y (2013) Regulatory T cells negatively affect IL-2 production of effector T cells through CD39/adenosine pathway in HIV infection. PLoS Pathog 9(4):e1003319. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Moir S, Fauci AS (2014) B-cell exhaustion in HIV infection: the role of immune activation. Curr Opin HIV AIDS 9:472–477. CrossRefPubMedGoogle Scholar
  93. 93.
    Rosser EC, Mauri C (2015) Regulatory B cells: origin, phenotype, and function. Immunity 42:607–612. CrossRefPubMedGoogle Scholar
  94. 94.
    Liu J, Zhan W, Kim CJ, Clayton K, Zhao H, Lee E, Cao JC, Ziegler B, Gregor A, Yue FY, Huibner S, MacParland S, Schwartz J, Song HH, Benko E, Gyenes G, Kovacs C, Kaul R, Ostrowski M (2014) IL-10-producing B cells are induced early in HIV-1 infection and suppress HIV-1-specific T cell responses. PLoS One 9(2):e89236. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Saze Z, Schuler PJ, Hong C-S, Cheng D, Jackson EK, Whiteside TL (2013) Adenosine production by human B cells and B cell–mediated suppression of activated T cells. Blood 122:9–18. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Kim E-S, Ackermann C, Tóth I, Dierks P, Eberhard JM, Wroblewski R, Scherg F, Geyer M, Schmidt RE, Beisel C, Bockhorn M, Haag F, van Lunzen J, Schulze zur Wiesch J (2017) Down-regulation of CD73 on B cells of patients with viremic HIV correlates with B cell activation and disease progression. J Leukoc Biol 101:1263–1271. CrossRefPubMedGoogle Scholar
  97. 97.
    Kaku H, Cheng KF, Al-Abed Y, Rothstein TL (2014) A novel mechanism of B-cell mediated immune suppression through CD73-expression and adenosine production. J Immunol 193:5904–5913. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Sauer AV, Brigida I, Carriglio N, Aiuti A (2012) Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol 3:265. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Hovi T, Smyth JF, Allison AC, Williams SC (1976) Role of adenosine deaminase in lymphocyte proliferation. Clin Exp Immunol 23:395–403PubMedPubMedCentralGoogle Scholar
  100. 100.
    Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I, Zavialov AV (2016) Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell Mol Life Sci 74(3):555–570. CrossRefPubMedGoogle Scholar
  101. 101.
    Martinez-Navio JM, Casanova V, Pacheco R, Naval-Macabuhay I, Climent N, Garcia F, Gatell JM, Mallol J, Gallart T, Lluis C, Franco R (2011) Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells. J Leukoc Biol 89:127–136. CrossRefPubMedGoogle Scholar
  102. 102.
    Tardif V, Gary E, Muir R et al (2017) Adenosine DeAminase (ADA) as an adjuvant molecule for human HIV-1 vaccine. J Immunol 198:225.15Google Scholar
  103. 103.
    Tsuboi I, Sagawa K, Shichijo S, Yokoyama MM, Ou DW, Wiederhold MD (1995) Adenosine deaminase isoenzyme levels in patients with human T-cell lymphotropic virus type 1 and human immunodeficiency virus type 1 infections. Clin Diagn Lab Immunol 2:626–630PubMedPubMedCentralGoogle Scholar
  104. 104.
    Gakis C, Calia G, A N et al (1989) Serum adenosine deaminase activity in HIV positive patients. pdf Panminerva Med 3:107–113Google Scholar
  105. 105.
    Franco R, Valenzuela A, Lluis C, Blanco J (1998) Enzymatic and extraenzymatic role of ecto-adenosine deaminase in lymphocytes. Immunol Rev 161:27–42. CrossRefPubMedGoogle Scholar
  106. 106.
    Pacheco R, Martinez-Navio JM, Lejeune M, Climent N, Oliva H, Gatell JM, Gallart T, Mallol J, Lluis C, Franco R (2005) CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proc Natl Acad Sci U S A 102:9583–9588. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Climent N, Martinez-Navio JM, Gil C, Garcia F, Rovira C, Hurtado C, Miralles L, Gatell JM, Gallart T, Mallol J, Lluis C, Franco R (2009) Adenosine deaminase enhances T-cell response elicited by dendritic cells loaded with inactivated HIV. Immunol Cell Biol 87:634–639. CrossRefPubMedGoogle Scholar
  108. 108.
    Casanova V, Naval-Macabuhay I, Massanella M, Rodríguez-García M, Blanco J, Gatell JM, García F, Gallart T, Lluis C, Mallol J, Franco R, Climent N, McCormick PJ (2012) Adenosine deaminase enhances the immunogenicity of human dendritic cells from healthy and HIV-infected individuals. PLoS One 7:e51287. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Martinez-navio JM, Climent N, Gallart T et al (2011) An old enzyme for current needs: adenosine deaminase and a dendritic cell vaccine for HIV. Immunol Cell Biol 90:594–600. CrossRefPubMedGoogle Scholar
  110. 110.
    Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393:648–659. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Valenzuela A, Blanco J, Callebaut C et al (1997) Adenosine deaminase binding to human CD26 is inhibited by HIV-1 envelope glycoprotein gp120 and viral particles. J Immunol 158:3721–3729PubMedGoogle Scholar
  112. 112.
    Blanco J, Valenzuela A, Herrera C et al (2000) The HIV-1 gp120 inhibits the binding of adenosine deaminase to CD26 by a mechanism modulated by CD4 and CXCR4 expression. FEBS Lett 477:123–128. CrossRefPubMedGoogle Scholar
  113. 113.
    Pacheco R, Garcia F, Nomdedeu M et al (2009) Immunological dysfunction in HIV-1-infected individuals caused by impairment of adenosine deaminase-induced costimulation of T-cell activation. Immunology 128(3):393–404. CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Pirrone V, Libon DJ, Sell C, Lerner CA, Nonnemacher MR, Wigdahl B (2013) Impact of age on markers of HIV-1 disease. Future Virol 8:81–101. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Iñigo MA, de Tejada M, Torres-Tortosa M et al (1992) Serum adenosine deaminase in human immunodeficiency virus infection. Its relationship with CD4+ lymphocytes and beta 2-microglobulin. Med Clin (Barc) 99:766–768Google Scholar
  116. 116.
    Pérez DOC, Menéndez MM, Irazabal C et al (1996) Adenosine deaminase (ADA) and beta 2-microglobulin (beta 2M) as discriminating serum markers of progression to AIDS. An Med Interna 13:217–221Google Scholar
  117. 117.
    Lakshmi LJ, Zephy D, Bhaskar MV (2013) Adenosine deaminase activity in HIV positive cases. Int J Bioassays 02:1553–1556. CrossRefGoogle Scholar
  118. 118.
    Ipp H, Zemlin AE, Glashoff RH, van Wyk J, Vanker N, Reid T, Bekker LG (2013) Serum adenosine deaminase and total immunoglobulin G correlate with markers of immune activation and inversely with CD4 counts in asymptomatic, treatment-naive HIV infection. J Clin Immunol 33:605–612. CrossRefPubMedGoogle Scholar
  119. 119.
    Carrera J, Porras JA, Vidal F, Pinto B, Richart C (1995) Evaluation of serum adenosine deaminase as a prognostic marker in the treatment of human immunodeficiency virus infection with zidovudine. Revista clinica espanola, Rev Clin Esp 195:74–77PubMedGoogle Scholar
  120. 120.
    Abdi M, Rahbari R, Khatooni Z, Naseri N, Najafi A, Khodadadi I (2016) Serum adenosine deaminase (ADA) activity: a novel screening test to differentiate HIV monoinfection from HIV-HBV and HIV-HCV coinfections. J Clin Lab Anal 30:200–203. CrossRefPubMedGoogle Scholar
  121. 121.
    Niedzwicki JG, Mayer KH, Abushanab E, Abernethy DR (1991) Plasma adenosine deaminase, is a marker for human immunodeficiency virus-I seroconversion. Am Hematol 37:152–155CrossRefGoogle Scholar
  122. 122.
    Niedzwicki JG, Kouttab NM, Mayer KH, Carpenter CC, Parks RE Jr, Abushanab E, Abernethy DR (1991) Plasma adenosine deaminase2: a marker for human immunodeficiency virus infection. J Acquir Immune Defic Syndr 4:178–182PubMedGoogle Scholar
  123. 123.
    Chittiprol S, Satishchandra P, Bhimasenarao RS, Rangaswamy GR, Sureshbabu SV, Subbakrishna DK, Satish KS, Desai A, Ravi V, Shetty KT (2007) Plasma adenosine deaminase activity among HIV1 clade C seropositives: relation to CD4 T cell population and antiretroviral therapy. Clin Chim Acta 377:133–137. CrossRefPubMedGoogle Scholar
  124. 124.
    Murray L, Loftin C, Gwyneth C (1985) Elevated activity adenosine deaminase and purine nucleoside phosphorylase in peripheral blood null lymphocytes from patients with acquired immune deficiency syndrome. Blood 65:1318–1323PubMedGoogle Scholar
  125. 125.
    Cowan MJ, Bradyt R, Widdert KJ (1986) Elevated erythrocyte adenosine deaminase activity in patients with acquired immunodeficiency syndrome. Proc Natl Acad U S A 83:1089–1091CrossRefGoogle Scholar
  126. 126.
    Casoli C, Lisa A, Magnani G et al (1995) Prognostic value of adenosine deaminase compared to other markers for progression to acquired immunodeficiency syndrome among intravenous drug users. J Med Virol 45(2):203–210CrossRefGoogle Scholar
  127. 127.
    Hunt PW, Lee SA, Siedner MJ (2016) Immunologic biomarkers, morbidity, and mortality in treated HIV infection. J Infec Dis 214(2):44–50. CrossRefGoogle Scholar
  128. 128.
    Lederman MM, Funderburg NT, Sekaly RP et al (2013) Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 119:51–83. CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Craveiro M, Clerc I, Sitbon M, Taylor N (2013) Metabolic pathways as regulators of HIV infection. Curr Opin HIV AIDS 8(3):182–189. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da SaúdeUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e ExatasUniversidade Federal de Santa MariaSanta MariaBrazil
  3. 3.Laboratório de Enzimologia Toxicológica (ENZITOX), Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e ExatasUniversidade Federal de Santa MariaSanta MariaBrazil

Personalised recommendations