The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 12-19 , July 2008

Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease

  • Susan Moir, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: Susan Moir, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 6A02, Bethesda, MD 20892.
    • ,
  • Anthony S. Fauci, MD

Received 3 March 2008 ,Revised 24 April 2008 ,Accepted 25 April 2008.

References 

  1. De Milito A. B lymphocyte dysfunctions in HIV infection. Curr HIV Res. 2004;2:11–21
  2. Fauci AS, Mavilio D, Kottilil S. NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol. 2005;5:835–843
  3. Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med. 2006;12:289–295
  4. Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol. 2004;2:E20
  5. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983;309:453–458
  6. Ng VL. B-lymphocytes and autoantibody profiles in HIV disease. Clin Rev Allergy Immunol. 1996;14:367–384
  7. Racz P, Tenner-Racz K, van Vloten F, Schmidt H, Dietrich M, Gluckman JC, et al. Lymphatic tissue changes in AIDS and other retrovirus infections: tools and insights. Lymphology. 1990;23:85–91
  8. Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, et al. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994;140:105–130
  9. Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, Ehler LA, et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A. 2001;98:10362–10367
  10. Fournier AM, Fondere JM, Alix-Panabieres C, Merle C, Baillat V, Huguet MF, et al. Spontaneous secretion of immunoglobulins and anti-HIV-1 antibodies by in vivo activated B lymphocytes from HIV-1-infected subjects: monocyte and natural killer cell requirement for in vitro terminal differentiation into plasma cells. Clin Immunol. 2002;103:98–109
  11. Shirai A, Cosentino M, Leitman-Klinman SF, Klinman DM. Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J Clin Invest. 1992;89:561–566
  12. Martinez-Maza O, Breen EC. B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol. 2002;14:528–532
  13. Chong Y, Nabeshima S, Furusyo N, Murata M, Yamaji K, Hayashi J. Downregulation of CXCR5 in CD27- B cells of HIV-1 infected patients. J Med Virol. 2004;73:362–367
  14. Jacobson MA, Khayam-Bashi H, Martin JN, Black D, Ng V. Effect of long-term highly active antiretroviral therapy in restoring HIV-induced abnormal B-lymphocyte function. J Acquir Immune Defic Syndr. 2002;31:472–477
  15. Nilssen DE, Oktedalen O, Brandtzaeg P. Intestinal B cell hyperactivity in AIDS is controlled by highly active antiretroviral therapy. Gut. 2004;53:487–493
  16. Notermans DW, de Jong JJ, Goudsmit J, Bakker M, Roos MT, Nijholt L, et al. Potent antiretroviral therapy initiates normalization of hypergammaglobulinemia and a decline in HIV type 1-specific antibody responses. AIDS Res Hum Retroviruses. 2001;17:1003–1008
  17. Morris L, Binley JM, Clas BA, Bonhoeffer S, Astill TP, Kost R, et al. HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy. J Exp Med. 1998;188:233–245
  18. Moir S, Malaspina A, Pickeral OK, Donoghue ET, Vasquez J, Miller NJ, et al. Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J Exp Med. 2004;200:587–599
  19. Margolick JB, Munoz A, Donnenberg AD, Park LP, Galai N, Giorgi JV, et al. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort Study. Nat Med. 1995;1:674–680
  20. Malaspina A, Moir S, Ho J, Wang W, Howell ML, O'Shea MA, et al. Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc Natl Acad Sci U S A. 2006;103:2262–2267
  21. Moir S, Malaspina A, Li Y, Chun TW, Lowe T, Adelsberger J, et al. B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med. 2000;192:637–646
  22. Stoiber H, Speth C, Dierich MP. Role of complement in the control of HIV dynamics and pathogenesis. Vaccine. 2003;21(suppl 2):S77–S82
  23. Malaspina A, Moir S, Nickle DC, Donoghue ET, Ogwaro KM, Ehler LA, et al. Human immunodeficiency virus type 1 bound to B cells: relationship to virus replicating in CD4+ T cells and circulating in plasma. J Virol. 2002;76:8855–8863
  24. Rickert RC. Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. Curr Opin Immunol. 2005;17:237–243
  25. Dorner T, Radbruch A. Antibodies and B cell memory in viral immunity. Immunity. 2007;27:384–392
  26. Berberian L, Goodglick L, Kipps TJ, Braun J. Immunoglobulin VH3 gene products: natural ligands for HIV gp120. Science. 1993;261:1588–1591
  27. Juompan L, Lambin P, Zouali M. Selective alterations of the antibody response to HIV-1. Appl Biochem Biotechnol. 1998;75:139–150
  28. Scamurra RW, Miller DJ, Dahl L, Abrahamsen M, Kapur V, Wahl SM, et al. Impact of HIV-1 infection on VH3 gene repertoire of naive human B cells. J Immunol. 2000;164:5482–5491
  29. Margolin DH, Reimann KA, Sodroski J, Karlsson GB, Tenner-Racz K, Racz P, et al. Immunoglobulin V(H) usage during primary infection of rhesus monkeys with chimeric simian-human immunodeficiency viruses. J Virol. 1997;71:8582–8591
  30. De Milito A, Morch C, Sonnerborg A, Chiodi F. Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS. 2001;15:957–964
  31. Nagase H, Agematsu K, Kitano K, Takamoto M, Okubo Y, Komiyama A, et al. Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin Immunol. 2001;100:250–259
  32. Avery DT, Ellyard JI, Mackay F, Corcoran LM, Hodgkin PD, Tangye SG. Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J Immunol. 2005;174:4034–4042
  33. Anderson SM, Tomayko MM, Shlomchik MJ. Intrinsic properties of human and murine memory B cells. Immunol Rev. 2006;211:280–294
  34. Klein U, Rajewsky K, Kuppers R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998;188:1679–1689
  35. Moir S, Malaspina A, Ho J, Wang W, DiPoto AC, O'Shea MA, et al. Normalization of B cell counts and subpopulations following antiretroviral therapy in chronic HIV disease. J Infect Dis. 2008;197:572–579
  36. D'Orsogna LJ, Krueger RG, McKinnon EJ, French MA. Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy. AIDS. 2007;21:1747–1752
  37. Chong Y, Ikematsu H, Kikuchi K, Yamamoto M, Murata M, Nishimura M, et al. Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug-naive and HAART-treated HIV type 1-infected patients. AIDS Res Hum Retroviruses. 2004;20:219–226
  38. Titanji K, Chiodi F, Bellocco R, Schepis D, Osorio L, Tassandin C, et al. Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS. 2005;19:1947–1955
  39. Ehrhardt GR, Hsu JT, Gartland L, Leu CM, Zhang S, Davis RS, et al. Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells. J Exp Med. 2005;202:783–791
  40. Moir S, Ho J, Malaspina A, Wang W, DiPoto A, O'Shea MA, et al. Evidence for HIV-associated B-cell exhaustion in a dysfunctional memory B-cell compartment in HIV-infected viremic individuals. J Exp Med. 2008;In press
  41. Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105:4390–4398
  42. Cuss AK, Avery DT, Cannons JL, Yu LJ, Nichols KE, Shaw PJ, et al. Expansion of functionally immature transitional B cells is associated with human-immunodeficient states characterized by impaired humoral immunity. J Immunol. 2006;176:1506–1516
  43. Malaspina A, Moir S, Chaitt DG, Rehm CA, Kottilil S, Falloon J, et al. Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood. 2007;109:2086–2088
  44. Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001;7:73–79
  45. Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, et al. A potential role for interleukin-7 in T-cell homeostasis. Blood. 2001;97:2983–2990
  46. McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001;410:974–979
  47. Siegel RM. Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol. 2006;6:308–317
  48. Ho J, Moir S, Malaspina A, Howell ML, Wang W, DiPoto AC, et al. Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc Natl Acad Sci U S A. 2006;103:19436–19441
  49. Bekker V, Scherpbier H, Beld M, Piriou E, van Breda A, Lange J, et al. Epstein-Barr virus infects B and non-B lymphocytes in HIV-1-infected children and adolescents. J Infect Dis. 2006;194:1323–1330
  50. Soriano-Sarabia N, Leal M, Delgado C, Molina-Pinelo S, De Felipe B, Ruiz-Mateos E, et al. Effect of hepatitis C virus coinfection on humoral immune alterations in naive HIV-infected adults on HAART: a three year follow-up study. J Clin Immunol. 2005;25:296–302
  51. De Boer RJ, Mohri H, Ho DD, Perelson AS. Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol. 2003;170:2479–2487
  52. Hazenberg MD, Stuart JW, Otto SA, Borleffs JC, Boucher CA, de Boer RJ, et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood. 2000;95:249–255
  53. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med. 2001;194:1731–1741
  54. Lempicki RA, Kovacs JA, Baseler MW, Adelsberger JW, Dewar RL, Natarajan V, et al. Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc Natl Acad Sci U S A. 2000;97:13778–13783
  55. Mohri H, Bonhoeffer S, Monard S, Perelson AS, Ho DD. Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science. 1998;279:1223–1227
  56. Sachsenberg N, Perelson AS, Yerly S, Schockmel GA, Leduc D, Hirschel B, et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J Exp Med. 1998;187:1295–1303
  57. Der SD, Zhou A, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A. 1998;95:15623–15628
  58. Samuelsson A, Sonnerborg A, Heuts N, Coster J, Chiodi F. Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 1997;13:1031–1038
  59. Muro-Cacho CA, Pantaleo G, Fauci AS. Analysis of apoptosis in lymph nodes of HIV-infected persons: intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J Immunol. 1995;154:5555–5566
  60. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–548
  61. Malaspina A, Moir S, Kottilil S, Hallahan CW, Ehler LA, Liu S, et al. Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J Immunol. 2003;170:5965–5972
  62. Moir S, Ogwaro KM, Malaspina A, Vasquez J, Donoghue ET, Hallahan CW, et al. Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. Proc Natl Acad Sci U S A. 2003;100:6057–6062
  63. Malaspina A, Moir S, Orsega SM, Vasquez J, Miller NJ, Donoghue ET, et al. Compromised B cell responses to influenza vaccination in HIV-infected individuals. J Infect Dis. 2005;191:1442–1450
  64. Titanji K, De Milito A, Cagigi A, Thorstensson R, Grutzmeier S, Atlas A, et al. Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. Blood. 2006;108:1580–1587
  65. Hart M, Steel A, Clark SA, Moyle G, Nelson M, Henderson DC, et al. Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J Immunol. 2007;178:8212–8220
  66. Kruetzmann S, Rosado MM, Weber H, Germing U, Tournilhac O, Peter HH, et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med. 2003;197:939–945
  67. Shearer WT, Easley KA, Goldfarb J, Rosenblatt HM, Jenson HB, Kovacs A, et al. Prospective 5-year study of peripheral blood CD4, CD8, and CD19/CD20 lymphocytes and serum Igs in children born to HIV-1 women. The P(2)C(2) HIV Study Group. J Allergy Clin Immunol. 2000;106:559–566
  68. Bekker V, Scherpbier H, Pajkrt D, Jurriaans S, Zaaijer H, Kuijpers TW. Persistent humoral immune defect in highly active antiretroviral therapy-treated children with HIV-1 infection: loss of specific antibodies against attenuated vaccine strains and natural viral infection. Pediatrics. 2006;118:e315–e322
  69. Bliss SJ, O'Brien KL, Janoff EN, Cotton MF, Musoke P, Coovadia H, et al. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis. 2008;8:67–80
  70. Obaro SK, Pugatch D, Luzuriaga K. Immunogenicity and efficacy of childhood vaccines in HIV-1-infected children. Lancet Infect Dis. 2004;4:510–518
  71. Dankner WM, Lindsey JC, Levin MJ. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J. 2001;20:40–48
  72. Hatherill M. Sepsis predisposition in children with human immunodeficiency virus. Pediatr Crit Care Med. 2005;6:S92–S98
  73. Mascola JR, Lewis MG, Stiegler G, Harris D, VanCott TC, Hayes D, et al. Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol. 1999;73:4009–4018
  74. Miller CJ, Genesca M, Abel K, Montefiori D, Forthal D, Bost K, et al. Antiviral antibodies are necessary for control of simian immunodeficiency virus replication. J Virol. 2007;81:5024–5035
  75. Baba TW, Liska V, Hofmann-Lehmann R, Vlasak J, Xu W, Ayehunie S, et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med. 2000;6:200–206
  76. Johnston MI, Fauci AS. An HIV vaccine: evolving concepts. N Engl J Med. 2007;356:2073–2081
  77. Letvin NL. Progress and obstacles in the development of an AIDS vaccine. Nat Rev Immunol. 2006;6:930–939
  78. Montefiori D, Sattentau Q, Flores J, Esparza J, Mascola J. Antibody-based HIV-1 vaccines: recent developments and future directions. PLoS Med. 2007;4:e348
  79. Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med. 2007;13:1032–1034
  80. Karlsson Hedestam GB, Fouchier RA, Phogat S, Burton DR, Sodroski J, Wyatt RT. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol. 2008;6:143–155

 (Supported by an educational grant from Merck & Co., Inc.)Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

 Terms in boldface and italics are defined in the glossary on page 13.

PII: S0091-6749(08)00776-8

doi: 10.1016/j.jaci.2008.04.034

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 12-19 , July 2008

Article Tools

* Image Usage & Resolution