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Disorders of immune reconstitution in patients with HIV infection responding to antiretroviral therapy

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Abstract

Patients with HIV infection who were very immunodeficient before achieving a virologic response to antiretroviral therapy (ART) may experience various disorders of immune reconstitution. Immune restoration disease occurs in approximately 10% to 50% of patients and results from the restoration of a pathogen-specific immune response that causes immunopathology and presents as tissue inflammation or cellular proliferative disease. Opportunistic infections occur in no more than 5% of patients, but approximately one half of these patients have higher than expected CD4 T-cell counts and appear to have residual immune dysfunction. Autoimmune disease may arise because the reconstituted immune system confers an increased susceptibility to immune dysregulation but there may be different mechanisms because Graves’ disease presents after a median time of about 2 years of ART whereas systemic lupus erythematosus presents earlier. Persistent CD4 T-cell deficiency (< 500/μL) affects up to 60% of patients and appears to reflect depletion of the naïve T-cell pool that results from low production and/or increased turnover of cells.

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References and Recommended Reading

  1. Stone SF, Price P, French MA: Cytomegalovirus (CMV)-specific CD8+ T cells in individuals with HIV infection: correlation with protection from CMV disease. J Antimicrob Chemother 2006, 57:585–588.

    Article  PubMed  CAS  Google Scholar 

  2. French MA, Lenzo N, John M, et al.: Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000, 1:107–115.

    Article  PubMed  CAS  Google Scholar 

  3. French MA, Price P, Stone SF: Immune restoration disease after antiretroviral therapy. AIDS 2004, 18:1615–1627.

    Article  PubMed  CAS  Google Scholar 

  4. Schrier RD, Song MK, Smith IL, et al.: Intraocular viral and immune pathogenesis of immune recovery uveitis in patients with healed cytomegalovirus retinitis. J Ret Vitreous Dis 2006, 26:165–169.

    Google Scholar 

  5. Stone SF, Price P, Tay-Kearney M-L, French MA: Cytomegalovirus (CMV) retinitis immune restoration disease occurs during HAART-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment. J Infect Dis 2002, 185:1813–1817.

    Article  PubMed  CAS  Google Scholar 

  6. Stone SF, Lee S, Keane NM, et al.: Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 (dipeptidyl peptidase IV) enzyme activity with hepatotoxicity after highly active antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients. J Infect Dis 2002, 186:1498–1502.

    Article  PubMed  CAS  Google Scholar 

  7. Connick E, Kane MA, White IE, et al.: Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma during potent antiretroviral therapy. Clin Infect Dis 2004, 39:1852–1855.

    Article  PubMed  Google Scholar 

  8. Phillips P, Bonner S, Gataric N, et al.: Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005, 41:1483–1497.

    Article  PubMed  Google Scholar 

  9. Bower M, Nelson M, Young AM, et al.: Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 2005, 23:5224–5228.

    Article  PubMed  CAS  Google Scholar 

  10. Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005, 5:361–373.

    Article  PubMed  Google Scholar 

  11. French MA: The immunopathogenesis of mycobacterial immune restoration disease. Lancet Infect Dis 2006, 6:461–462.

    Article  PubMed  Google Scholar 

  12. Hoffmann C, Horst H-A, Albrecht H, Schlote W: Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral therapy. J Neurol Neurosurg Psychiatry 2003, 74:1142–1144.

    Article  PubMed  CAS  Google Scholar 

  13. Clark BM, Krueger RG, Price P, French MA: Compartmentalization of the immune response in varicella zoster virus immune restoration disease causing transverse myelitis. AIDS 2004, 18:1218–1221.

    Article  PubMed  Google Scholar 

  14. Phillips P, Walker B, Joy R, et al.: Comparison of histopathologic findings in non-tuberculous mycobacterial immune reconstitution syndrome (NTM-IRS), disseminated MAC (DMAC), and tuberculosis (MTb) [abstract THPE0082]. Presented at the XVI International AIDS Conference. Toronto, Canada; August 13–18, 2006.

  15. Foudraine NA, Hovenkamp E, Notermans DW, et al.: Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients. AIDS 1999, 13:177–184.

    Article  PubMed  CAS  Google Scholar 

  16. Bourgarit A, Carcelain G, Martinez V, et al.: Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006, 20:F1–7.

    PubMed  CAS  Google Scholar 

  17. Posada-Vegara MP, Lindoso J, Tolezano JE, et al.: Tegumentary Leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome in 2 patients with AIDS. J Infec Dis 2005, 192:1819–1822.

    Article  Google Scholar 

  18. Breton G, Adle-Biassette H, Therby A, et al.: Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 2006, 20:119–132.

    Article  PubMed  Google Scholar 

  19. Jenny-Avital ER, Abadi M: Immune reconstitution cryptoccosis after initiation of successful highly active antiretroviral therapy. Clin Infect Dis 2002, 35:e128–e133.

    Article  PubMed  Google Scholar 

  20. Lortholary O, Fontanet A, Memain N et al.: Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005, 19:1043–1049.

    Article  PubMed  Google Scholar 

  21. Miralles P, Berenguer J, Lacruz C: Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. AIDS 2001, 15:1900–1902.

    Article  PubMed  CAS  Google Scholar 

  22. Vendrely A, Bienvenu B, Gasnault J: Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol 2005, 109:449–455.

    Article  PubMed  CAS  Google Scholar 

  23. Domingo P, Torres OH, Ris J, et al.: Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection. Am J Med 2001, 110:605–609.

    Article  PubMed  CAS  Google Scholar 

  24. Stone SF, Price P, Keane NM, et al.: Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART. HIV Med 2002, 3:21–27.

    Article  PubMed  CAS  Google Scholar 

  25. Xie J, Pan H, Yoo S, Gao SJ: Kaposi’s sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol 2005, 79:15027–15037.

    Article  PubMed  CAS  Google Scholar 

  26. Price P, Morahan G, Huang D, et al.: Polymorphisms in cytokine genes define sub-populations of HIV-1 patients who experienced immune restoration diseases. AIDS 2002, 16:2043–2047.

    Article  PubMed  CAS  Google Scholar 

  27. Mills KH: Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 2004, 4:841–855.

    Article  PubMed  CAS  Google Scholar 

  28. Kumarasamy N, Chaguturu S, Myer KH et al.: Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Aquir Immune Defic Syndr 2004, 37:1574–1576.

    Article  CAS  Google Scholar 

  29. Breton G, Dvual X, Estellat C et al.: Determinants of immune reconstitution inflammatory syndrome in HIV type-1-infected patient with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004, 39:1709–1712.

    Article  PubMed  Google Scholar 

  30. Shelburne SA, Darcourt J, White C, et al.: The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005, 40:1049–1052.

    Article  PubMed  Google Scholar 

  31. Price P, Keane NM, Stone SF, et al.: MHC haplotypes affect the expression of opportunistic infections in HIV patients. Hum Immunol 2001, 62:157–164.

    Article  PubMed  CAS  Google Scholar 

  32. Ratnam I, Chiu C, Kandala NB, Easterbrook PJ: Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin Infect Dis 2006, 42:418–427.

    Article  PubMed  CAS  Google Scholar 

  33. Lawn SD, Myer L, Orrell C, et al.: Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS 2005, 19:2141–2148.

    Article  PubMed  Google Scholar 

  34. Braitstein P, Brinkhof MW, Dabis F, et al.: Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet 2006, 367:817–824. [Published erratum appears in Lancet 2006, 367:1902].

    Article  PubMed  Google Scholar 

  35. Etard JF, Ndiaye I, Thierry-Mieg M, et al.: Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study. AIDS 2006, 20:1181–1189.

    Article  PubMed  Google Scholar 

  36. Lesho E: Evidence base for using corticosteroids to treat HIV-associated immune reconstitution syndrome. Exper Rev Anti Infect Ther 2006, 4:469–478.

    Article  CAS  Google Scholar 

  37. Kirk O, Reiss P, Uberti-Foppa C, et al.: Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002, 137:239–250.

    PubMed  Google Scholar 

  38. Koletar SL, Williams PL, Wu J, et al.: Long-term follow-up of HIV-infected individuals who have significant increases in CD4+ cell counts during antiretroviral therapy. Clin Infect Dis 2004, 39:1500–1506.

    Article  PubMed  Google Scholar 

  39. Komanduri KV, Feinberg J, Hutchins RK, et al.: Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T-cell counts and recurrent retinitis. J Infect Dis 2001, 183:1285–1289.

    Article  PubMed  CAS  Google Scholar 

  40. French MA, Keane NM, McKinnon EJ, et al.: Susceptibility to opportunistic infections in HIV patients with increased CD4+ T-cells on ART may be predicted by markers of effector-memory CD4+ T-cell and B-cell dysfunction. HIV Med 2007, In press.

  41. Calza L, Manfredi R, Colangeli V, et al.: Systemic and discoid lupus erythematosus in HIV-infected patients treated with highly active antiretroviral therapy. Int J STD AIDS 2003, 14:356–359.

    Article  PubMed  Google Scholar 

  42. Piliero PJ, Fish DG, Preston S, et al.: Guillain-Barre syndrome associated with immune reconstitution. Clin Infect Dis 2003, 36:e111–e114.

    Article  PubMed  Google Scholar 

  43. Crum NF, Ganesan A, Johns ST, Wallace MR: Graves disease: an increasingly recognised immune reconstitution syndrome. AIDS 2006, 20:466–469.

    Article  PubMed  Google Scholar 

  44. Chen F, Day SL, Metcalfe RA, et al.: Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine 2005, 84:98–106.

    Article  PubMed  CAS  Google Scholar 

  45. French MA, Lewin SR, Dykstra C, et al.: Graves’ disease during immune reconstitution after highly active antiretroviral therapy for HIV infection: evidence of thymus dysfunction. AIDS Res Hum Retrovir 2004, 20:157–162.

    Article  PubMed  CAS  Google Scholar 

  46. Foulon G, Wislez M, Naccache JM, et al.: Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004, 38:418–425.

    Article  PubMed  Google Scholar 

  47. Bilu D, Mamelak AJ, Nguyen RH, et al.: Clinical and epidemiologic characterization of photosensitivity in HIV-positive individuals. Photodermatol Photoimmunol Photomed 2004, 20:175–183.

    Article  PubMed  Google Scholar 

  48. Kaufmann GR, Furrer H, Lederberger B, et al.: Characteristics, determinants, and clinical relevance of CD4 T cell recovery to < 500 cells/μL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 2005, 41:361–372.

    Article  PubMed  Google Scholar 

  49. Dronda F, Moreno S, Moreno A, et al.: Long-term outcomes among antiretroviral-naïve human immunodeficiency virus-infected patients with small increases in CD4+ cell counts after successful virologic suppression. Clin Infect Dis 2002, 35:1005–1009.

    Article  PubMed  Google Scholar 

  50. Harris JM, Hazenberg MD, Poulin J-F, et al.: Multiparameter evaluation of human thymic function, interpretations and caveats. Clin Immunol 2005, 115:138–146.

    Article  PubMed  CAS  Google Scholar 

  51. Mascio MD, Sereti I, Matthews LT, et al.: Naïve T cell dynamics in human immunodeficiency virus type 1 infection: effects of highly active antiretroviral therapy provide insights into the mechanisms of naïve T cell depletion. J Virol 2006, 80:2665–2674.

    Article  PubMed  CAS  Google Scholar 

  52. Mussini C, Pinti M, Borghi V, et al.: Features of ‘CD4-exploders’, HIV-positive patients with an optimal immune reconstitution after potent antiretroviral therapy. AIDS 2002, 16:1609–1616.

    Article  PubMed  Google Scholar 

  53. Fernandez S, Nolan R, Price P, et al.: Thymic function in severely immunodeficient HIV-1 infected patients receiving stable and effective antiretroviral therapy. AIDS Res Hum Retrovir 2006, 22:163–170.

    Article  PubMed  CAS  Google Scholar 

  54. Schacker TW, Brenchley JM, Beilman GJ, et al.: Lymphatic tissue fibrosis is associated with reduced numbers of naïve CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol 2006, 13:556–560.

    Article  PubMed  CAS  Google Scholar 

  55. Goicoechea M, Smith DM, Liu L, et al.: Determinants of CD4+ T cell recovery during suppressive antiretroviral therapy: association of immune activation, T cell maturation markers, and cellular HIV-1 DNA. J Infect Dis 2006, 194:29–37.

    Article  PubMed  Google Scholar 

  56. Hunt PW, Martin JN, Sinclair E, et al.: T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003, 187:1534–1543.

    Article  PubMed  CAS  Google Scholar 

  57. Benveniste O, Flahault A, Rollot F, et al.: Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J Infect Dis 2005, 191:1670–1679.

    Article  PubMed  Google Scholar 

  58. Nasi M, Pinti M, Bugarnini R, et al.: Genetic polymorphisms of Fas (CD95) and Fas ligand (CD178) influence the rise in CD4+ T cell count after antiretroviral therapy in drug-naïve HIV-positive patients. Immunogenetics 2005, 57:628–635.

    Article  PubMed  CAS  Google Scholar 

  59. Fernandez S, Rosenow AA, James IR, et al.: Recovery of CD4+ T-cells in HIV patients with a stable virological response to antiretroviral therapy is associated with polymorphisms of IL-6 and central major histocompatibility complex genes. J Acquir Immunodef Synd 2006, 41:1–5.

    Article  CAS  Google Scholar 

  60. Fernandez S, Price P, McKinnon EJ, et al.: Low CD4+ T cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T cell activation and senescence but not with lower effector memory T cell function. Clin Immunol 2006, 120:163–170.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Martyn A. French MD.

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French, M.A. Disorders of immune reconstitution in patients with HIV infection responding to antiretroviral therapy. Curr HIV/AIDS Rep 4, 16–21 (2007). https://doi.org/10.1007/s11904-007-0003-z

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