Skip to main content

Advertisement

Log in

Immune reconstitution and the consequences for opportunistic infection treatment and prevention

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Effective antiretroviral therapy that suppresses HIV replication is associated with dramatic increases in CD4 counts. Recent evidence suggests that this CD4 cell increase is biphasic in nature, with an initial phase (in the first 2 to 3 months) that represents redistribution of lymphocytes into the periphery and a second phase that is associated with true immunologic recovery and reconstitution. Immunologically there is evidence of increase in naive T cells, recovery of in vitro responses to microbial antigens, and repair of the damaged diversity of T cells. Clinically, this immune recovery has been characterized by decreasing morbidity and mortality from opportunistic infections, an ability to treat previously intractable infections, immune-mediated syndromes, and increasing reports of the ability to discontinue primary and secondary prophylaxis. Although there are still unresolved questions about the completeness of the immune recovery, most available evidence suggests in most patients the degree of immune reconstitution with effective antiretroviral therapy is sufficient to be protective against most opportunistic infections, and ultimately additional antimicrobial prophylaxis will be unnecessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Carpenter CC, Fischl MA, Hammer SM, et al.: Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. JAMA 1998, 280:78–86.

    Article  PubMed  CAS  Google Scholar 

  2. Report of the NIH Panel To Define Principles of Therapy of HIV Infection. Ann Intern Med 1998, 128:1057–1078.

  3. Gulick RM, Mellors JW, Havlir D, et al.: Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997, 337:734–739.

    Article  PubMed  CAS  Google Scholar 

  4. Shearer G, Clerici M: Early T-helper cell defects in HIV infection. AIDS 1991, 5:245–253.

    Article  PubMed  CAS  Google Scholar 

  5. Dolan MJ, Clerici M, Blatt SP, et al.: In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus. J Infect Dis 1995, 172:79–87.

    PubMed  CAS  Google Scholar 

  6. Connors M, Kovacs JA, Krevat S, et al.: HIV infection induces changes in CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nature Med 1997, 3:533–540.

    Article  PubMed  CAS  Google Scholar 

  7. Roederer M, Dubs JG, Anderson MT, et al.: CD8 naïve T Cell counts decrease progressively in HIV-infected adults. J Clin Invest 1995, 95:2061–2066.

    Article  PubMed  CAS  Google Scholar 

  8. Kestens L, Vanham G, Vereecken C, et al.: Selective increase of activation antigens HLA-DR and CD38 on CD4+ CD45RO+ T lymphocytes during HIV-1 infection. Clin Exp Immunol 1994, 95:436–441.

    Article  PubMed  CAS  Google Scholar 

  9. Autran B, Carcelain G, Li TS, et al.: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997, 277:112–116. The first paper to clearly show that effective control of HIV infection was associated with both quantitative and qualitative immunologic improvement.

    Article  PubMed  CAS  Google Scholar 

  10. Gorochov G, Neumann AU, Kereveur A, et al.: Pertubation of CD4+ and CD8+T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nature Medicine 1998, 4:215–221. This paper provides evidence that the immunologic improvement seen with effective antiretroviral therapy is associated with repair of the immune system, ie, immune reconstruction.

    Article  PubMed  CAS  Google Scholar 

  11. Lederman MM, Connick E, Landay A, et al.: Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine and ritonavir: results of AIDS Clinical Trial Group protocol 315. J Infect Dis 1998, 178:70–79.

    PubMed  CAS  Google Scholar 

  12. Gray CM, Schapiro JM, Winters MA, Merigan TC: Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience. AIDS Res Hum Retroviruses 1998, 14:561–569.

    PubMed  CAS  Google Scholar 

  13. Powderly WG, Landay A, Lederman MM: Recovery of the immune system with antiretroviral therapy, The end of opportunism? JAMA 1998, 280:72–77.

    Article  PubMed  CAS  Google Scholar 

  14. Gulick RM, Mellors JW, Havlir D, et al.: Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up. JAMA 1998, 280:35–41.

    Article  PubMed  CAS  Google Scholar 

  15. Notermans DW, Jurriaans S, de Wolf F, et al.: Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. Ritonavir/3TC/ZDV Study Group. AIDS 1998, 12:167–173.

    Article  PubMed  CAS  Google Scholar 

  16. Zhang ZQ, Notermans DW, Sedgewick G, et al.: Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc Natl Acad Sci U S A 1998, 95:1154–1159.

    Article  PubMed  CAS  Google Scholar 

  17. Li TS, Tubiana R, Katlama C, et al.: Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998, 351:1682–1686. Comparing responders to antiretroviral therapy with nonresponders, this study showed a greater increase in CD4 count, an early increase in memory CD4 T cells with a later increase of naive T cells, and sustained recovery of CD4 T-cell reactivity against opportunistic pathogens.

    Article  PubMed  CAS  Google Scholar 

  18. Rinaldo Jr CR, Liebmann JM, Huang XL, et al.: Prolonged suppression of human immunodeficiency virus type 1 (HIV-1) viremia in persons with advanced disease results in enhancement of CD4 T cell reactivity to microbial antigens but not to HIV-1 antigens. J Infect Dis 1999, 179:329–336.

    Article  PubMed  Google Scholar 

  19. Kostense S, Raaphorst FM, Notermans DW, et al.: Diversity of the T-cell receptor BV repertoire in HIV-1-infected patients reflects the biphasic CD4+ T-cell repopulation kinetics during highly active antiretroviral therapy. AIDS 1998, 12:F235-F240.

    Article  PubMed  CAS  Google Scholar 

  20. Pallela FJ, Delaney KM, Moorman AC, et al.: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998, 338:853–860. This multi-center US study showed that the incidence of any of three major opportunistic infections (P. carinii pneumonia, MAC disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997.The declines in morbidity and mortality due to AIDS were clearly shown to be attributable to the use of more intensive antiretroviral therapies.

    Article  Google Scholar 

  21. Clifford DB, Yiannoutsos C, Glicksman M, et al.: Highly active antiretroviral therapy improves prognosis in HIV associated progressive multifocal leukoencephalopathy. Neurology, in press.

  22. Valdez H, Gripshover BM, Salata RA, Lederman MM: Resolution of azole-resistant oropharyngeal candidiasis after initiation of potent combination antiretroviral therapy. AIDS 1998, 12:538.

    PubMed  CAS  Google Scholar 

  23. Carr A, Marriott D, Field A: Treatment of HIV-1 associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998, 351:256–261.

    Article  PubMed  CAS  Google Scholar 

  24. Michelet C, Arvieux C, Francois C, et al.: Opportunistic infections occuring during highly active antiretroviral treatment. AIDS 1998, 12:1815–1822.

    Article  PubMed  CAS  Google Scholar 

  25. Rodriguez-Rosado R, Soriano V, Dona C, Gonzalez-Lahoz J: Opportunistic infections shortly after beginning highly active antiretroviral therapy. Antiviral Therapy 1998, 3:229–231.

    PubMed  CAS  Google Scholar 

  26. Jacobson MA, Zegans M, Paven PR, et al.: Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997, 349:1443–1445. One of the first papers to show that the early immunologic effects of HAART may not provide sufficient protection to prevent opportunisitic infections (in this case CMV retinitis) in patients who have very low CD4 counts when therapy is started.

    Article  PubMed  CAS  Google Scholar 

  27. Race EM, Adelson-Mitty J, Kriegel GR, et al.: Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet 1998, 351:252–255.

    Article  PubMed  CAS  Google Scholar 

  28. Sepkowitz K: Effect of HAART on natural history of AIDSrelated opportunistic disorders. Lancet 1998, 351:228–230.

    Article  PubMed  CAS  Google Scholar 

  29. Narita M, Ashkin D, Hollender ES, et al.: Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998, 158:157–161. Thirty-six percent of HIV-positive patients with tuberculosis who were treated simultaneously for both tuberculosis and HIV experienced transient worsening of tuberculous symptomatology and lesions following antituberculous therapy. The majority of these also converted their skin tests from negative to strongly positive, suggesting that this paradoxicial worsening was associated with recovery of immunity to mycobacterial antigens.

    PubMed  CAS  Google Scholar 

  30. USPHS/IDSA prevention of Opportunistic Infections Working Group: 1997 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR 1997, 46:1–46.

    Google Scholar 

  31. Schneider MME, Borleffs JCC, Stolk RP, et al.: Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1 infected patients treated with highly active antiretroviral therapy. Lancet 1999, 353:201–203. Although small, this is the first published study to support the discontinuation of PCP prophylaxis in patients treated with effective antiretroviral therapy. In this study, the criterion for discontinuation was a CD4 increase to above 200 cells/mm3.

    Article  PubMed  CAS  Google Scholar 

  32. Kaufmann D, Pantaleo G, Sudae P, et al.: CD4-cell count in HIV-1-infected individuals remaining viremic after highly active antiretroviral therapy: Swiss HIV Cohort Study. Lancet 1998, 351:723–724.

    Article  PubMed  CAS  Google Scholar 

  33. Whitcup SM, Fortin E, Nussenblatt RB, et al.: Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. JAMA 1997, 277:1519–1520.

    Article  PubMed  CAS  Google Scholar 

  34. Tural C, Romeu J, Sirera G, et al.: Long lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998, 177:1080–1083.

    Article  PubMed  CAS  Google Scholar 

  35. Macdonald JC, Torriani FJ, Morse LS, et al.: Lack of reactivation of cytomegalovirus retinitis after stopping maintenance therapy in AIDS patients with sustained elevation of T cells in response to highly active antiretroviral therapy. J Infect Dis 1998, 177:1182–1187.

    PubMed  CAS  Google Scholar 

  36. Aberg JA, Yajko DM, Jacobson MA: Eradication of disseminated Mycobacterium avium complex after twelve months anti-mycobacterial therapy and response to highly active antiretroviral therapy. J Infect Dis 1998, 178:1446–1449.

    Article  PubMed  CAS  Google Scholar 

  37. Centers for Diseases Control and Prevention: Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: Principles of therapy and revised recommendations. MMWR 1998, 47:1–51.

    Google Scholar 

  38. Keita-Perse O, Roger PM, Pradier C, et al.: Do viral load and CD8 cell count at initiation of tritherapy influence the increase of CD4 T-cell count? AIDS 1998, 12:F175-F179.

    Article  PubMed  CAS  Google Scholar 

  39. Cohen Stuart JW, Slieker WA, Rijkers GT et al.: Early recovery of CD4+ T lymphocytes in children on highly active antiretroviral therapy. Dutch study group for children with HIV infections. AIDS 1998, 12:2155–2159.

    Article  PubMed  CAS  Google Scholar 

  40. Komanduri KV, Viswanathan MN, Wieder ED et al.: Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998, 4:953–956.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Powderly, W.G. Immune reconstitution and the consequences for opportunistic infection treatment and prevention. Curr Infect Dis Rep 1, 99–104 (1999). https://doi.org/10.1007/s11908-999-0016-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-999-0016-4

Keywords

Navigation