Journal of Clinical Immunology

, Volume 25, Issue 2, pp 106–115 | Cite as

Lower CD4+ T Lymphocyte Nadirs May Indicate Limited Immune Reconstitution in HIV-1 Infected Individuals on Potent Antiretroviral Therapy: Analysis of Immunophenotypic Marker Results of AACTG 5067

  • Ronald D’Amico
  • Yijun Yang
  • Donna Mildvan
  • Scott R. Evans
  • Carol T. Schnizlein-Bick
  • Richard Hafner
  • Nancy Webb
  • Michael Basar
  • Robert Zackin
  • Mark A. Jacobson


Background: Although initiation of potent antiretroviral therapy (ART) has significantly improved immune perturbations in individuals with AIDS, it is unclear which factors are most important in determining the degree of immune reconstitution.

Methods: Whole blood was analyzed at baseline and week 12 in six groups of subjects (n = 81): those with acute or following immune reconstitution after Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia (PcP) (two groups) and cytomegalovirus (CMV) retinitis (two groups), HIV-infection without AIDS (one group), and healthy volunteers (one group). Absolute CD4+ and CD8+ T lymphocytes, naíve (CD45RA+) and memory (CD45RO+) CD4+ T lymphocytes and percentages of activated CD8+ T lymphocytes (CD8+/CD38+/HLA-DR), and CD28 expression on CD4+ and CD8+ T lymphocytes were enumerated.

Results: The reconstituted CMV group, which had a history of a lower CD4+ T lymphocyte nadir compared to the reconstituted PcP group (15 cells/mm3 versus 48 cells/mm3; p = .013), had significantly lower absolute CD4+, CD8+ and naíve CD4+ T lymphocytes and a trend toward lower memory CD4+ T lymphocytes compared to the reconstituted PcP group. Moreover, no difference was noted between the reconstituted groups in the proportion of subjects with undetected HIV-1 RNA. The reconstituted subjects had significantly lower absolute CD4+, memory CD4+ and naíve CD4+ T lymphocytes than the HIV-positive controls and a significantly higher percentage of activated CD8+ T lymphocytes with a lower percentage of CD8+CD28 expression than the HIV-negative controls.

Conclusion: The association of CD4+ T lymphocyte nadir with the extent of immune reconstitution in HIV-infected individuals suggests that HIV-1 may cause irreparable immune system damage despite potent ART.


Immune reconstitution CD4 nadir opportunistic infection antiretroviral therapy 


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  1. 1.
    Moore RD, Keruly JC, Chaisson RE: Decline in CMV and other opportunistic diseases with combination antiretroviral therapy [abstract 184]. In Program and Abstracts of the Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, Illinois, February 1–5, 1998Google Scholar
  2. 2.
    Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New Engl J Med 338:853–860, 1998Google Scholar
  3. 3.
    Chiasson MA, Berenson L, Li W, Schwartz S, Singh T, Forlenza S, Mojica BA, Hamburg MA: Declining HIV/AIDS mortality in New York City. J Acquir Immune Defic Syndr 21:59–64, 1999Google Scholar
  4. 4.
    Hengel RL, Kovacs JA: Surrogate markers of immune function in human immunodeficiency virus-infected patients: What are they surrogates for? J Infect Dis 188:1791–1793, 2003Google Scholar
  5. 5.
    Kelleher AD, Carr A, Zaunders J, Cooper DA: Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. J Infect Dis 173:321–329, 1996Google Scholar
  6. 6.
    Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277:112–116, 1997Google Scholar
  7. 7.
    Lederman M, Connick E, Landay A, Kuritzkes D, Spritzler J, St Clair M, Kotzin B, Fox L, Heath-Chiozzi M, Leonard J, Rousseau F, Wade M, D’Arc-Roe J, Martinez A, Kessler H: Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: Results of the AIDS Clinical trial group protocol 315. J Infect Dis 178:70–79, 1998Google Scholar
  8. 8.
    Lederman HM, Williams PL, Wu JW, Evans TG, Cohn SE, McCutchan JA, Koletar SL, Hafner R, Connick E, Valentine FT, McElrath MJ, Roberts NJ, Currier JS, for the AIDS Clinical Trials Group 889 Study Team: Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4+ cell depletion. J Infect Dis 188:1794–1803, 2003Google Scholar
  9. 9.
    Pakker NG, Kroon E, Roos M, Otto S, Hall D, Wit F, Hamann D, van der Ende M, Claessen F, Kauffmann R, Koopmans P, Kroon F, ten Napel C, Sprenger H, Weigel H, Montaner J, Lange J, Reiss P, Schellekens P, Miedema F for the INCAS Study Group: Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. AIDS 13:203–212, 1999Google Scholar
  10. 10.
    Mezzaroma I, Carlesimo M, Pinter E, Alario C, Sacco G, Muratori S, Bernardi M, Paganelli R, Aiuti F: Long-term evaluation of T-cell subsets and T-cell function after HAART in advanced stage HIV-1 disease. AIDS 13:1187–1193, 1999Google Scholar
  11. 11.
    Gea-Banacloche JC, Lane HC: Immune reconstitution in HIV infection. AIDS 13(A): S25–S38, 1999Google Scholar
  12. 12.
    Valdez H, Connick E, Smith K, Lederman MM, Bosch R, Kim R, St Clair M, Kuritzkes D, Kessler H, Fox L, Blanchard-Vargas M, Landay A for the AIDS clinical trials group protocol 375 team: Limited immune restoration after 3 years’ suppression of HIV-1 replication in patients with moderately advanced disease. AIDS 16:1859–1866, 2002Google Scholar
  13. 13.
    Bucy RP, Hockett RD, Derdeyn CA, Saag MS, Squires K, Sillers M, Mitsuyasu RT, Kilby JM: Initial increase in blood CD4+ lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest 103:1391–1398, 1999Google Scholar
  14. 14.
    Lederman MM, Valdez H: Immune restoration with antiretroviral therapies: Implications for clinical management. JAMA 284(2):223–228, 2000Google Scholar
  15. 15.
    Choremi-Papadopoulou H, Panagiootou N, Samouilidou E, Kontopidou F, Viglis V, Antoniadou A, Kosmidis J, Kordossis T: CD28 co-stimulation and CD28 expression in T lymphocyte subsets in HIV-1 infection with and without progression to AIDS. Clin Exp Immunol 119:499–506, 2000Google Scholar
  16. 16.
    Koretzky GA, Peterson EJ: T cell activation and inactivation. In Clinical Immunology: Principles and Practice, Robert Rich (ed). UK, Mosby International Limited, 2001, Section 1, Chapter 10, pp 10.1–10.15Google Scholar
  17. 17.
    Ostrowski S, Gerstoft J, Pedersen B, Ullum H: A low level of CD4+CD28+ T cells is an independent predictor of high mortality in human immunodeficiency virus type 1-infected patients. J Infect Dis 187:1726–1734, 2003Google Scholar
  18. 18.
    Lange CG, Lederman MM, Medvik K, Asaad R, Wild M, Kalayjian R, Valdez H: Nadir CD4+ T-cell count and numbers of CD28+CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS 17:2015–2023, 2003Google Scholar
  19. 19.
    Koletar SL, Heald AE, Finkelstein D, Hafner R, Currier JS, McCutchan JA, Vallee M, Torriani FJ, Powderly WG, Fass RJ, Murphy RL for the ACTG 888 Study Team: A prospective study of discontinuing primary and secondary Pneumocystis carinii prophylaxis after CD4+ counts increase to >200 cells/mm3. AIDS 15:1509–1515, 2001Google Scholar
  20. 20.
    Tortajada C, Garcia F, Plana M, Gallart T, Maleno M, Miro J, Gatell J: Comparison of T-cell subsets’ reconstitution after 12 months of highly active antiretroviral therapy initiated during early versus advanced states of HIV disease. J Acquir Immune Defic Syndr 25:296–305, 2000Google Scholar
  21. 21.
    Kaufmann GR, Zaunders J, Cunningham P, Kelleher A, Grey P, Smith D, Carr A, Cooper D: Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection. AIDS 14:2643–2651, 2000Google Scholar
  22. 22.
    Miller V, Mocroft A, Reiss P, Katlama C, Papadopoulos A, Katzenstein T, van Lunzen J, Antunes F, Phillips A, Lundgren J for the EuroSIDA study group: Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: Results from the EuroSIDA study. Ann Intern Med 130:570–577, 1999Google Scholar
  23. 23.
    Lange CG, Valdez H, Medvik K, Asaad R, Lederman MM: CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on phenotypic and functional immune restoration in HIV-1 infection. Clin Immunol 102(2):154–161, 2002Google Scholar
  24. 24.
    Pakker NG, Roos MT, van Leeuwen R, de Jong MD, Koot M, Reiss P, Lange JM, Miedema F, Danner SA, Schellekens PT: Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents. J Acquir Immune Defic Syndr Human Retro 16:318–326, 1997Google Scholar
  25. 25.
    Li TS, Tubiana R, Katlama C, Calvez V, Mohand H, Autran B: Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351:1682–1686, 1998Google Scholar
  26. 26.
    Lederman M, McKinnis R, Kelleher D, Cutrell A, Mellors J, Niesler M, Cooney E, Haas D, Haubrich R, Stanford J, Horton J, Landay A, Spreen W: Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: Age inversely predicts naíve CD4 cell count increase. AIDS 14:2635–2642, 2000Google Scholar
  27. 27.
    Valdez H, Smith KY, Landay A, Connick E, Kuritzkes D, Kessler H, Fox L, Spritzler J, Roe J, Lederman MB, Lederman HM, Evans T, Heath-Chiozzi M, Lederman MM, and the ACTG 375 team: Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. AIDS 14:11–21, 2000Google Scholar
  28. 28.
    Egger M, May M, Chene G, Phillips A, Ledergerber B, Dabis F, Costagliola D, Monforte A, deWolf F, Reiss P, Lundgren J, Justice A, Staszewski S, Leport C, Hogg R, Sabin C, Gill M, Salzberger B, Sterne J, and the ART Cohort Collaboration: Prognosis of HIV-1 infected patients starting highly active antiretroviral therapy: A collaborative analysis of prospective studies. Lancet 360:119–127, 2002Google Scholar
  29. 29.
    Brinchmann JE, Dobloug JH, Heger BH, Haaheim LL, Sannes M, Egeland T: Expression of costimulatory molecule CD28 on T cells in human immunodeficiency virus type 1 infection: Functional and clinical correlations. J Infect Dis 169:730–738, 1994Google Scholar
  30. 30.
    Roos MT, Miedema F, Meinesz AP, DeLeeuw NA, Pakker NG, Lange JM, Coutinho RA, Schellekens PT: Low T cell reactivity to combined CD3 plus CD28 stimulation is predictive for progression to AIDS: Correlation with decreased CD28 expression. Clin Exp Immunol 105:409–415, 1996Google Scholar
  31. 31.
    Sondergaard SR, Aladdin H, Ullum H, Gerstoft J, Skinhoj P, Pedersen B: Immune function and phenotype before and after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 21:376–383, 1999Google Scholar
  32. 32.
    Hakki M, Riddell S, Storek J, Carter R, Stevens-Ayers T, Sudour P, White K, Corey L, Boeckh M: Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: Impact of host factors, drug therapy, and subclinical reactivation. Blood 102:3060–3067, 2003Google Scholar
  33. 33.
    Ware R: Immune abnormalities secondary to infectious diseases. In Clinical Immunology: Principles and Practice, Robert Rich (ed). UK, Mosby International Limited, 2001, Section 4, Chapter 43, pp 43.1–43.7Google Scholar
  34. 34.
    Marcotte H, Levesque D, Delanay K, Bourgeault A, de la Durantaye R, Brochu S, Lavoie M: Pneumocystis carinii infection in transgenic B cell-deficient mice. J Infect Dis 173:1034–1037, 1996Google Scholar
  35. 35.
    Walzer PD, Schnelle V, Armstrong D, Rosen PP: The nude mouse: A new experimental model for Pneumocystis carinii infection. Science 197:177–179, 1977Google Scholar
  36. 36.
    Walzer PD: Immunopathogenesis or Pneumocystis carinii infection. J Lab Clin Med 118:206–216, 1991Google Scholar
  37. 37.
    Harmsen AG, Stankiewicz M: Requirement for CD4+ cells in resistance to Pneumocystis carinii pneumonia in mice. J Exp Med 172:937–945, 1990Google Scholar
  38. 38.
    Kulke MH, Vance EA: Pneumocystis carinii pneumonia in patients receiving chemotherapy for breast cancer. Clin Infect Dis 25:215–218, 1997Google Scholar
  39. 39.
    Smith D, Neal J, Holmberg S, and the Centers for Disease Control Idiopathic CD4+ T- lymphocytopenia task force: Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV infection. New Engl J Med 328:373–379, 1999Google Scholar
  40. 40.
    Phair J, Munoz A, Detels R: The risk of Pneumocystis carinii pneumonia among men infected with immunodeficiency virus type 1. New Engl J Med 322:161–165, 1990Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Ronald D’Amico
    • 1
    • 7
  • Yijun Yang
    • 2
  • Donna Mildvan
    • 1
  • Scott R. Evans
    • 2
  • Carol T. Schnizlein-Bick
    • 3
  • Richard Hafner
    • 4
  • Nancy Webb
    • 5
  • Michael Basar
    • 5
  • Robert Zackin
    • 2
  • Mark A. Jacobson
    • 6
  1. 1.Beth Israel Medical CenterNew York
  2. 2.Harvard School of Public HealthBoston
  3. 3.Indiana University School of MedicineIndianapolis
  4. 4.Division of AIDSNational Institutes of HealthBethesda
  5. 5.Frontier Science and technology Research FoundationAmherst
  6. 6.Positive Health Program, Department of MedicineUniversity of California San Francisco and The Medical Service, San Francisco, General HospitalSan Francisco
  7. 7.Beth Israel Medical CenterNew York

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