Springer Seminars in Immunopathology

, Volume 18, Issue 3, pp 305–322 | Cite as

Studies on lymphoid tissue from HIV-infected individuals: implications for the design of therapeutic strategies

  • Oren J. Cohen
  • Giuseppe Pantaleo
  • Gordon K. Lam
  • Anthony S. Fauci


Lymphoid tissue is a major reservoir of human immunodeficiency virus (HIV) infection in vivo. In addition, the lymphoid microenvironment provides a replicative advantage to the virus in that it provides a milieu of activated target cells that allows for efficient virus spread. The process of mobilization and activation of immune competent cells directed against the virus paradoxically contributes to the propagation of virus replication. Disruption of the lymphoid microenvironment during the progression of HIV disease is a poorly understood process, which may be of considerable importance pathogenically. Studies of lymph node biopsy samples taken 8 weeks apart from individuals who did not undergo any change in their therapeutic regimen (i.e., patients who either remained untreated or remained on their ongoing nucleoside analogue reverse transcriptase inhibitor monotherapy regimen) revealed little change in histopathology or viral load over the 8-week period. These results with successive lymph node biopsy samples taken from different sites indicate that an isolated lymph node biopsy accurately reflects the pathologic process associated with HIV infection and that this process diffusely involves the lymphoid system. Treatment with reverse transcriptase inhibitor monotherapy of patients in relatively early stage HIV disease had no detectable impact on the viral load in lymphoid tissue, suggesting the need to investigate more potent antiretroviral regimens during this stage of disease. Among patients with moderately advanced HIV disease, switching to combination therapy from a monotherapy regimen resulted in decreased viral replication in lymph nodes; this effect was associated with decreases in plasma viremia. Despite the fact that measures of viral replication decreased significantly, the net frequency of HIV-infected cells in peripheral blood and lymph nodes remained unchanged. Potent antiretroviral drug combinations may be capable of profound and long-term down-regulation of plasma viremia. It will be essential to monitor the status of viral trapping, viral burden, and viral replication within lymphoid tissue during treatment with such drugs to determine accurately their true potential for impact on these key features of HIV pathogenesis.


Human Immunodeficiency Virus Lymphoid Tissue Nucleoside Analogue Human Immunodeficiency Virus Disease Plasma Viremia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fauci A, Schnittman S, Poli G, Koenig S, Pantaleo G (1991) Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection. Ann Intern Med 114:678Google Scholar
  2. 2.
    Bagnarelli P, Menzo S, Valenza A, et al (1992) Molecular profile of human immunodeficiency virus type 1 infection in symptomless patients and in patients with AIDS. J Virol 66:7328Google Scholar
  3. 3.
    Piatak M, Saag M, Yang L, et al (1993) High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259:1749Google Scholar
  4. 4.
    Pantaleo G, Graziosi C, Butini L, et al (1991) Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci USA 88:9838Google Scholar
  5. 5.
    Pantaleo G, Graziosi C, Demarest JF, et al (1993) HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362:355Google Scholar
  6. 6.
    Embretson J, Zupancic M, Ribas J, et al (1993) Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362:359Google Scholar
  7. 7.
    Wei X, Ghosh SK, Taylor ME, et al (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373:117Google Scholar
  8. 8.
    Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123Google Scholar
  9. 9.
    Cohen OJ, Pantaleo G, Holodniy M, et al (1995) Decreased HIV-1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue. Proc Natl Acad Sci USA 1995, 92:6017Google Scholar
  10. 10.
    Mondino A, Khoruts A, Jenkins M (1996) The anatomy of T-cell activation and tolerance. Proc Natl Acad Sci USA 93:2245Google Scholar
  11. 11.
    Pantaleo G, Graziosi C, Demarest JF, Cohen O, Vaccarezza M, Gantt K, et al (1994) Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev 140:105Google Scholar
  12. 12.
    Koup RA, Safrit JT, Cao Y, et al (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68:4650Google Scholar
  13. 13.
    Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB (1994) Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68:6103Google Scholar
  14. 14.
    Joling P, Bakker L, Van Strijp J, et al (1993) Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent. J Immunol 150:1065Google Scholar
  15. 15.
    Spiegel H, Herbst H, Niedobitek G, Foss H, Stein H (1992) Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol 140:15Google Scholar
  16. 16.
    Racz P, Tenner-Rácz K, Kahl C, et al (1986) Spectrum of morphologic changes of lymph nodes from patients with AIDS or AIDS-related complexes. Prog Allergy 37:81Google Scholar
  17. 17.
    Turner R, Levine A, Gill P, Parker J, Meyer P (1987) Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome. Am J Surg Pathol 11:625Google Scholar
  18. 18.
    Sei S, Akiyoshi H, Bernard J, et al (1996) Dynamics of virus versus host interaction in children with human immunodeficiency virus type 1 infection. J Infect Dis 173:1485Google Scholar
  19. 19.
    Heath SL, Tew JG, Tew JG, Szakal AK, Burton GF (1995) Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 377:740Google Scholar
  20. 20.
    Bukrinsky M, Stanwick T, Dempsey M, Stevenson M (1991) Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254:423Google Scholar
  21. 21.
    Ascher M, Sheppard H (1988) AIDS as immune system activation: a model for pathogenesis. Clin Exp Immunol 73:165Google Scholar
  22. 22.
    Bass H, Nishanian P, Hardy W, et al (1992) Immune changes in HIV infection: significant correlations and differences in serum markers and lymphoid phenotypic antigens. Clin Immunol Immunopathol 64:63Google Scholar
  23. 23.
    Sheppard HW, Ascher MS, McRae B, Anderson RE, Lang W, Allain JP (1991) The initial immune response to HIV and immune system activation determine the outcome of HIV disease. J Acquit Immune Defic Syndr 4:704Google Scholar
  24. 24.
    Fauci A (1988) The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science 239:617Google Scholar
  25. 25.
    Fauci A (1993) Multifactorial nature of human immunodeficiency virus diseases: implications for therapy. Science 262:1011Google Scholar
  26. 26.
    Rosenberg Z, Fauci A (1989) Induction of expression of HIV in latently or chronically infected cells. AIDS Res Hum Retroviruses 5:1Google Scholar
  27. 27.
    Poli G, Fauci AS (1993) Cytokine modulation of HIV expression. Semin Immunol 5:165Google Scholar
  28. 28.
    Graziosi C, Pantaleo G, Gantt KR, et al (1994) Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science 265:248Google Scholar
  29. 29.
    Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS (1990) HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61:213Google Scholar
  30. 30.
    Westermann J, Persin S, Matyas J, Meide P van der, Pabst R (1994) Migration of so-called naive and memory T lymphocytes from blood to lymph in the rat. The influence of IFN-gamma on the circulation pattern. J Immunol 152:1744Google Scholar
  31. 31.
    Sprenger R, Toellner K, Schmetz C, et al (1995) Follicular dendritic cells productively infected with immunodeficiency viruses transmit infection to T cells. Med Microbiol Immunol 184:129Google Scholar
  32. 32.
    Schmitz J, Lunzen J van, Tenner-Racz K, et al (1994) Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia. J Immunol 153:1352Google Scholar
  33. 33.
    Hivroz C, Mazerolles F, Soula M, et al (1993) Human immunodeficiency virus gp120 and derived peptides activate protein tyrosine kinase p56lck in human CD4 T lymphocytes. Eur J Immunol 23:600Google Scholar
  34. 34.
    Goldman F, Jensen W, Johnson G, Heasley L, Cambier J (1994) gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation. J Immunol 153:2905Google Scholar
  35. 35.
    Banda N, Bernier J, Kurahara D, et al (1992) Cross-linking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med 176:1099Google Scholar
  36. 36.
    Li C, Friedman D, Wang C, Metelev V, Pardee A (1995) Induction of apoptosis in uninfected lymphocytes by HIV-1 tat protein. Science 268:429Google Scholar
  37. 37.
    Westendorp M, Frank R, Ochsenbauer C, et al (1995) Sensitization of T cells to CD95-mediated apoptosis by HIV-1 tat and gp120. Nature 375:497Google Scholar
  38. 38.
    Howcroft T, Strebel K, Martin M, Singer D (1993) Repression of MHC class I gene promoter activity by two-exon tat of HIV. Science 260:1320Google Scholar
  39. 39.
    Dawson V, Dawson T, Uhl G, Snyder S (1993) Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary conical cultures. Proc Natl Acad Sci USA 90:3256Google Scholar
  40. 40.
    Pietraforte D, Tritarelli E, Testa U, Minetti M (1994) gp120 HIV envelope glycoprotein increases the production of nitric oxide in human monocyte-derived macrophages. J Leukoc Biol 55:175Google Scholar
  41. 41.
    Bukrinsky M, Nottet H, Schmidtmayerova H, et al (1995) Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-I)-infected monocytes: implications for HIV-associated neurological disease. J Exp Med 181:735Google Scholar
  42. 42.
    Weeks B, Klotman M, Holloway E, Stetler-Stevenson W, Kleinman H, Klotman P (1993) HIV-1 infection stimulates T cell invasiveness and synthesis of the 92-kDa type IV collagenase. AIDS Res Hum Retroviruses 9:513Google Scholar
  43. 43.
    Lafrenie R, Wahl L, Epstein J, Hewlett I, Yamada K, Dhawan S (1996) HIV-I tat modulates the function of monocytes and alters their interactions with microvessel endothelial cells. J Immunol 156:1638Google Scholar
  44. 44.
    Cohen O, Pantaleo G, Holodniy M, et al (1996) Antiretroviral monotherapy in early human immunodeficiency virus disease has no detectable effect on viral load in peripheral blood and lymph nodes. J Infect Dis 173:849Google Scholar
  45. 45.
    Biberfeld P, Chayt K, Marselle L, Biberfeld G, Gallo R, Harper M (1986) HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am J Pathol 125:436Google Scholar
  46. 46.
    Fox C, Tenner-Rácz K, Rácz P, Firpo A, Pizzo P, Fauci A (1991) Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis 164:1051Google Scholar
  47. 47.
    Burke AP, Anderson D, Mannan P, et al (1994) Systemic lymphadenopathic histology in human immunodeficiency virus-1-seropositive drug addicts without apparent acquired immunodeficiency syndrome. Hum Pathol 25:248Google Scholar
  48. 48.
    Fischl M, Richman D, Grieco M, et al (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317:185Google Scholar
  49. 49.
    Fischl M, Richman D, Hansen N, et al (1990) The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. Ann Intern Med 112:727Google Scholar
  50. 50.
    Volberding P, Lagakos S, Koch M, et al (1990) Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4 positive cells per cubic millimeter. N Engl J Med 322:941Google Scholar
  51. 51.
    Volberding P, Lagakos S, Grimes J, et al (1994) The duration of zidovudine benefit in persons with asymptomatic HIV infection. J Am Med Assoc 272:437Google Scholar
  52. 52.
    Vella S, Giuliano M, Dally L, et al (1994) Long-term follow-up of zidovudine therapy in asymptomatic HIV infection: results of a multicenter cohort study. J Acquir Immune Defic Syndr 7:31Google Scholar
  53. 53.
    Cooper D, Gatell J, Kroon S, et al (1993) Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter. N Engl J Med 329:297Google Scholar
  54. 54.
    Concorde Coordinating Committee (1994) Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 343:871Google Scholar
  55. 55.
    Volberding P, Lagakos S, Grimes J, et al (1995) A comparison of immediate with deferred zidovudine therapy for asyptomatic HIV- infected adults with CD4 cell counts of 500 or more per cubic millimeter. N Engl J Med 333:401Google Scholar
  56. 56.
    Choi S, Lagakos S, Schooley R, Volberding P (1993) CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine. Ann Intern Med 118:674Google Scholar
  57. 57.
    Armstrong J, Horne R (1984) Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet 11:370Google Scholar
  58. 58.
    Baroni C, Pezzella F, Mirolo M, Ruco L, Rossi G (1986) Immunohistochemical demonstration of p24 HTLV-III major core protein in different cell types within lymph nodes from patients with lymphadenopathy syndrome (LAS). Histopathology 10:5Google Scholar
  59. 59.
    Lafeuillade A, Poggi C, Profizi N, Tamalet C, Costes O (1996) Human immunodeficiency virus type 1 kinetics in lymph nodes compared with plasma. J Infect Dis 174:404Google Scholar
  60. 60.
    Mellors J Jr, CR, Gupta P, White R, Todd J, Kingsley L (1996) Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167Google Scholar
  61. 61.
    O'Brien W, Hartigan P, Martin D, et al (1996) Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 334:426Google Scholar
  62. 62.
    Sei S, Kleiner D, Kopp J, et al (1994) Quantitative analysis of viral burden in tissues from adults and children with symptomatic human immunodeficiency virus type 1 infection assessed by polymerase chain reaction. J Infect Dis 170:325Google Scholar
  63. 63.
    Perrin L, Yerly S, Lazzarin A, et al (1996) Reduced viremia and increased CD4/CD8 ratio in patients with primary HIV infection treated with AZT-ddl. Eleventh International Conference on AIDS, Vancouver, 1996. We.B. 532Google Scholar
  64. 64.
    Markowitz M, Cao Y, Hurley A, et al (1996) Triple therapy with AZT, 3TC, and ritonavir in 12 subjects newly infected with HIV-1. Eleventh International Conference on AIDS, Vancouver, 1996. Th.B. 933Google Scholar
  65. 65.
    Saimot AG, Simon F, Landman R, et al (1996) A triple nucleoside analogue combination in four patients with primary HIV-1 infections: towards complete virological remissions? Eleventh International Conference on AIDS, Vancouver, 1996. Mo.B. 1332Google Scholar
  66. 66.
    Kinloch-De Loes S, Hirschel BJ, Hoen B, et al (1995) A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 333:408Google Scholar
  67. 67.
    Perelson AS, Essungen P, Markowitz M, Ho DD (1996) How long should treatment be given if we had an antiretroviral regimen that completely blocks HIV replication? Eleventh International Conference on AIDS, Vancouver, 1996. Th.B. 930Google Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Oren J. Cohen
    • 1
  • Giuseppe Pantaleo
    • 1
  • Gordon K. Lam
    • 1
  • Anthony S. Fauci
    • 1
  1. 1.Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaUSA

Personalised recommendations