Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

B cells in HIV infection and disease

Nature Reviews Immunology volume 9, pages 235–245 (2009)Cite this article

Key Points

  • HIV infection leads to perturbations of all of the main cell types of the immune system, including B cells. Most B-cell perturbations are associated with indirect effects of ongoing HIV replication, although some perturbations arise regardless of the decrease in viraemia by effective antiretroviral therapy (ART).

  • Many B-cell defects in HIV infection are associated with alterations in the B-cell subpopulations that circulate in the peripheral blood. Most B cells in healthy individuals comprise resting naive and memory B cells, whereas several minor subpopulations are over-represented in HIV-infected individuals, including immature transitional B cells, exhausted B cells, activated mature B cells and plasmablasts.

  • In vitro and in vivo studies show that HIV can also interact directly with B cells, although the frequency of these interactions is unlikely to account for the extent of B-cell dysregulation that is observed in infected individuals. HIV virions complexed with complement and antibody can bind B cells through the complement receptor CD21, and HIV virions and proteins, including gp120 and Nef, can also interact directly or indirectly with B cells.

  • Indirect effects of HIV viraemia on B cells include B-cell hyperactivity (as manifested by hypergammaglobulinaemia), increased B-cell polyclonal activation, increased B-cell turnover, increased expression of activation markers and of markers that are associated with activation-induced apoptosis, increased frequency of B-cell malignancies and increased differentiation of B cells to plasmablasts.

  • HIV viraemia with CD4+ T-cell lymphopenia is associated with an increased frequency of immature transitional B cells. This increase is also associated with increased serum levels of interleukin-7.

  • HIV viraemia leads to B-cell exhaustion, as manifested by increased expression of multiple inhibitory receptors, altered expression of homing receptors, decreased cell division and somatic hypermutation in vivo, decreased proliferative and effector properties in vitro and enrichment of HIV-specific responses in the exhausted B-cell compartment.

  • Although most B-cell perturbations in HIV-infected individuals are attributed to viraemia and are reversible by ART, one important exception is the loss of memory B cells. All stages of HIV infection are associated with a decrease both in the frequency of resting memory B cells and of B-cell responses against T-cell-dependent and T-cell-independent antigens.

  • Many B-cell perturbations observed in HIV infection also arise in various infectious and non-infectious disease settings that involve immune dysfunction. Several human diseases that affect B cells show dysregulation of immature transitional B cells, whereas others show dysregulation of memory B cells, with alterations that are similar to B-cell exhaustion and activation-induced terminal differentiation.

Abstract

In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4+ T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: HIV-induced alterations of human B-cell subpopulations.
Figure 2: Direct and indirect effects of HIV replication on B cells.
Figure 3: B-cell exhaustion induced by persistent HIV infection and ongoing viral replication.

Similar content being viewed by others

References

  1. Lane, H. C. et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 309, 453–458 (1983). This study was the first to describe B-cell hyperactivity and dysfunction in individuals with AIDS.

    Article  CAS  PubMed  Google Scholar 

  2. Barre-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. Popovic, M., Sarngadharan, M. G., Read, E. & Gallo, R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224, 497–500 (1984).

    Article  CAS  PubMed  Google Scholar 

  4. Grossman, Z., Meier-Schellersheim, M., Paul, W. E. & Picker, L. J. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nature Med. 12, 289–295 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Sodora, D. L. & Silvestri, G. Immune activation and AIDS pathogenesis. AIDS 22, 439–446 (2008).

    Article  PubMed  Google Scholar 

  6. Ammann, A. J. et al. B-cell immunodeficiency in acquired immune deficiency syndrome. JAMA 251, 1447–1449 (1984).

    Article  CAS  PubMed  Google Scholar 

  7. Pahwa, S. G., Quilop, M. T., Lange, M., Pahwa, R. N. & Grieco, M. H. Defective B-lymphocyte function in homosexual men in relation to the acquired immunodeficiency syndrome. Ann. Intern. Med. 101, 757–763 (1984).

    Article  CAS  PubMed  Google Scholar 

  8. Carbone, A. et al. Lymph node immunohistology in intravenous drug abusers with persistent generalized lymphadenopathy. Arch. Pathol. Lab. Med. 109, 1007–1012 (1985).

    CAS  PubMed  Google Scholar 

  9. Kekow, J., Kern, P., Schmitz, H. & Gross, W. L. Abnormal B-cell response to T-cell-independent polyclonal B-cell activators in homosexuals presenting persistent generalized lymph node enlargement and HTLV-III antibodies. Diagn. Immunol. 4, 107–111 (1986).

    CAS  PubMed  Google Scholar 

  10. Schnittman, S. M., Lane, H. C., Higgins, S. E., Folks, T. & Fauci, A. S. Direct polyclonal activation of human B lymphocytes by the acquired immune deficiency syndrome virus. Science 233, 1084–1086 (1986).

    Article  CAS  PubMed  Google Scholar 

  11. Kacani, L. et al. Detachment of human immunodeficiency virus type 1 from germinal centers by blocking complement receptor type 2. J. Virol. 74, 7997–8002 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Moir, S. 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. 192, 637–646 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Malaspina, A. 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. 76, 8855–8863 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Thacker, T. C. et al. Follicular dendritic cells and human immunodeficiency virus type 1 transcription in CD4+ T cells. J. Virol. 83, 150–158 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Shen, L. & Siliciano, R. F. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J. Allergy Clin. Immunol. 122, 22–28 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rappocciolo, G. et al. DC-SIGN on B lymphocytes is required for transmission of HIV-1 to T lymphocytes. PLoS Pathog. 2, e70 (2006).

    Article  PubMed Central  PubMed  Google Scholar 

  17. He, B. et al. HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. J. Immunol. 176, 3931–3941 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Berberian, L., Goodglick, L., Kipps, T. J. & Braun, J. Immunoglobulin VH3 gene products: natural ligands for HIV gp120. Science 261, 1588–1591 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Moir, S. et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc. Natl Acad. Sci. USA 98, 10362–10367 (2001). By identifying terminally differentiated CD21low B cells in HIV-viraemic individuals, the authors provide insight into the hypergammaglobulinaemia that is associated with HIV disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Notermans, D. W. et al. Potent antiretroviral therapy initiates normalization of hypergammaglobulinemia and a decline in HIV type 1-specific antibody responses. AIDS Res. Hum. Retroviruses 17, 1003–1008 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Shearer, W. T. 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. J. Allergy Clin. Immunol. 106, 559–566 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Shirai, A., Cosentino, M., Leitman-Klinman, S. F. & Klinman, D. M. Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J. Clin. Invest. 89, 561–566 (1992). This study provides the first comprehensive analysis of HIV-induced B-cell hyperactivity at the cellular level.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Moir, S. et al. Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J. Exp. Med. 200, 587–599 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Kovacs, J. A. et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J. Exp. Med. 194, 1731–1741 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Malaspina, A. et al. Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J. Immunol. 170, 5965–5972 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. De Milito, A. et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 103, 2180–2186 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Martinez-Maza, O., Crabb, E., Mitsuyasu, R. T., Fahey, J. L. & Giorgi, J. V. Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity. J. Immunol. 138, 3720–3724 (1987).

    CAS  PubMed  Google Scholar 

  28. van der Meijden, M. et al. IL-6 receptor (CD126′IL-6R′) expression is increased on monocytes and B lymphocytes in HIV infection. Cell Immunol. 190, 156–166 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Nagase, H. et al. Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin. Immunol. 100, 250–259 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Conge, A. M. et al. Impairment of B-lymphocyte differentiation induced by dual triggering of the B-cell antigen receptor and CD40 in advanced HIV-1-disease. AIDS 12, 1437–1449 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Haynes, B. F. et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906–1908 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Ng, V. L. B-lymphocytes and autoantibody profiles in HIV disease. Clin. Rev. Allergy Immunol. 14, 367–384 (1996).

    Article  PubMed  Google Scholar 

  33. Martinez-Maza, O. & Breen, E. C. B-cell activation and lymphoma in patients with HIV. Curr. Opin. Oncol. 14, 528–532 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Mandl, J. N. et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nature Med. 14, 1077–1087 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Rieckmann, P., Poli, G., Fox, C. H., Kehrl, J. H. & Fauci, A. S. Recombinant gp120 specifically enhances tumor necrosis factor-alpha production and Ig secretion in B lymphocytes from HIV-infected individuals but not from seronegative donors. J. Immunol. 147, 2922–2927 (1991).

    CAS  PubMed  Google Scholar 

  36. Weimer, R. et al. HIV-induced IL-6/IL-10 dysregulation of CD4 cells is associated with defective B cell help and autoantibody formation against CD4 cells. Clin. Exp. Immunol. 111, 20–29 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Muller, F., Aukrust, P., Nordoy, I. & Froland, S. S. Possible role of interleukin-10 (IL-10) and CD40 ligand expression in the pathogenesis of hypergammaglobulinemia in human immunodeficiency virus infection: modulation of IL-10 and Ig production after intravenous Ig infusion. Blood 92, 3721–3729 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Diop, O. M. et al. Plasmacytoid dendritic cell dynamics and α interferon production during Simian immunodeficiency virus infection with a nonpathogenic outcome. J. Virol. 82, 5145–5152 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med. 12, 1365–1371 (2006). References 37 and 39 indicate potential mediators of B-cell hyperactivity in HIV-infected individuals with chronic viraemia.

    Article  CAS  PubMed  Google Scholar 

  40. Brenchley, J. M., Price, D. A. & Douek, D. C. HIV disease: fallout from a mucosal catastrophe? Nature Immunol. 7, 235–239 (2006).

    Article  CAS  Google Scholar 

  41. Wagner, M. et al. IL-12p70-dependent Th1 induction by human B cells requires combined activation with CD40 ligand and CpG DNA. J. Immunol. 172, 954–963 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Swingler, S. et al. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature 424, 213–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Swingler, S. et al. Evidence for a pathogenic determinant in HIV-1 Nef involved in B cell dysfunction in HIV/AIDS. Cell Host Microbe 4, 63–76 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Qiao, X. et al. Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nature Immunol. 7, 302–310 (2006). References 42–44 identify potential mechanisms of Nef-mediated B-cell hyperactivity and dysfunction in HIV-infected individuals.

    Article  CAS  Google Scholar 

  45. Giri, M. S., Nebozhyn, M., Showe, L. & Montaner, L. J. Microarray data on gene modulation by HIV-1 in immune cells: 2000–2006. J. Leukoc. Biol. 80, 1031–1043 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Napolitano, L. A. et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nature Med. 7, 73–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Fry, T. J. et al. A potential role for interleukin-7 in T-cell homeostasis. Blood 97, 2983–2990 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. LeBien, T. W. & Tedder, T. F. B lymphocytes: how they develop and function. Blood 112, 1570–1580 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Malaspina, A. et al. Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc. Natl Acad. Sci. USA 103, 2262–2267 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Malaspina, A. et al. Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood 109, 2086–2088 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Moir, S. & Fauci, A. S. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J. Allergy Clin. Immunol. 122, 12–19 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Moir, S. et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J. Exp. Med. 205, 1797–1805 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Gallimore, A. et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I–peptide complexes. J. Exp. Med. 187, 1383–1393 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Med. 12, 1198–1202 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Kaufmann, D. E. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nature Immunol. 8, 1246–1254 (2007).

    Article  CAS  Google Scholar 

  57. Ehrhardt, G. R. et al. Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells. J. Exp. Med. 202, 783–791 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Ehrhardt, G. R. et al. Discriminating gene expression profiles of memory B cell subpopulations. J. Exp. Med. 205, 1807–1817 (2008). References 52, 57 and 58 describe distinct memory B cells that might have immunoregulatory roles in health and disease.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Klein, U. & Dalla-Favera, R. Germinal centres: role in B-cell physiology and malignancy. Nature Rev. Immunol. 8, 22–33 (2008).

    Article  CAS  Google Scholar 

  61. Cagigi, A. et al. Altered expression of the receptor-ligand pair CXCR5/CXCL13 in B-cells during chronic HIV-1 infection. Blood 112, 4401–4410 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Shin, H. & Wherry, E. J. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408–415 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Morris, L. et al. HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy. J. Exp. Med. 188, 233–245 (1998). This study was the first to describe changes in B-cell responses after effective ART.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Nilssen, D. E., Oktedalen, O. & Brandtzaeg, P. Intestinal B cell hyperactivity in AIDS is controlled by highly active antiretroviral therapy. Gut 53, 487–493 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Fournier, A. M. et al. Dynamics of spontaneous HIV-1 specific and non-specific B-cell responses in patients receiving antiretroviral therapy. AIDS 16, 1755–1760 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Jacobson, M. A., Khayam-Bashi, H., Martin, J. N., 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. 31, 472–477 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Horvath, A. et al. High level of anticholesterol antibodies (ACHA) in HIV patients. Normalization of serum ACHA concentration after introduction of HAART. Immunobiology 203, 756–768 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Malaspina, A. et al. CpG oligonucleotides enhance proliferative and effector responses of B cells in HIV-infected individuals. J. Immunol. 181, 1199–1206 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Jiang, W. et al. Impaired naive and memory B-cell responsiveness to TLR9 stimulation in human immunodeficiency virus infection. J. Virol. 82, 7837–7845 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Moir, S. et al. Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. Proc. Natl Acad. Sci. USA 100, 6057–6062 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. De Boer, R. J., Mohri, H., Ho, D. D. & Perelson, A. S. Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J. Immunol. 170, 2479–2487 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Silvestri, G., Paiardini, M., Pandrea, I., Lederman, M. M. & Sodora, D. L. Understanding the benign nature of SIV infection in natural hosts. J. Clin. Invest. 117, 3148–3154 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Kaur, A. et al. Dynamics of T- and B-lymphocyte turnover in a natural host of simian immunodeficiency virus. J. Virol. 82, 1084–1093 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Ribeiro, R. M. Dynamics of CD4+ T cells in HIV-1 infection. Immunol. Cell Biol. 85, 287–294 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Bekker, V. et al. Epstein–Barr virus infects B and non-B lymphocytes in HIV-1-infected children and adolescents. J. Infect. Dis. 194, 1323–1330 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Moir, S. et al. Normalization of B cell counts and subpopulations following antiretroviral therapy in chronic HIV disease. J. Infect. Dis. 197, 572–579 (2008).

    Article  PubMed  Google Scholar 

  77. Meira, D. G., Lorand-Metze, I., Toro, A. D., Silva, M. T. & Vilela, M. M. Bone marrow features in children with HIV infection and peripheral blood cytopenias. J. Trop. Pediatr. 51, 114–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Le Guillou-Guillemette, H. et al. Immune restoration under HAART in patients chronically infected with HIV-1: diversity of T, B, and NK immune responses. Viral Immunol. 19, 267–276 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Lederman, M. M. Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 15, S11–S15 (2001).

    Article  Google Scholar 

  80. Gougeon, M. L. et al. Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J. Immunol. 156, 3509–3520 (1996).

    CAS  PubMed  Google Scholar 

  81. Ho, J. et al. Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc. Natl Acad. Sci. USA 103, 19436–19441 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Herbeuval, J. P. & Shearer, G. M. HIV-1 immunopathogenesis: how good interferon turns bad. Clin. Immunol. 123, 121–128 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Titanji, K. et al. Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS 19, 1947–1955 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Titanji, K. et al. Low frequency of plasma nerve-growth factor detection is associated with death of memory B lymphocytes in HIV-1 infection. Clin. Exp. Immunol. 132, 297–303 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Chong, Y. 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 20, 219–226 (2004).

    Article  PubMed  Google Scholar 

  86. De Milito, A. B lymphocyte dysfunctions in HIV infection. Curr. HIV Res. 2, 11–21 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Cagigi, A., Nilsson, A., De Milito, A. & Chiodi, F. B cell immunopathology during HIV-1 infection: lessons to learn for HIV-1 vaccine design. Vaccine 26, 3016–3025 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Tarlinton, D. B-cell memory: are subsets necessary? Nature Rev. Immunol. 6, 785–790 (2006).

    Article  CAS  Google Scholar 

  89. D'Orsogna, L. J., Krueger, R. G., McKinnon, E. J. & French, M. A. Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy. AIDS 21, 1747–1752 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Jacobsen, M. C. et al. Pediatric human immunodeficiency virus infection and circulating IgD+ memory B cells. J. Infect. Dis. 198, 481–485 (2008).

    Article  PubMed  Google Scholar 

  91. De Milito, A., Morch, C., Sonnerborg, A. & Chiodi, F. Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS 15, 957–964 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Hart, M. 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. 178, 8212–8220 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Malaspina, A. et al. Compromised B cell responses to influenza vaccination in HIV-infected individuals. J. Infect. Dis. 191, 1442–1450 (2005).

    Article  PubMed  Google Scholar 

  94. Titanji, K. et al. Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. Blood 108, 1580–1587 (2006). This study shows the early and sustained impairment of memory B-cell responses in HIV-infected individuals.

    Article  CAS  PubMed  Google Scholar 

  95. Tejiokem, M. C. et al. HIV-infected children living in central Africa have low persistence of antibodies to vaccines used in the expanded program on immunization. PLoS ONE 2, e1260 (2007).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  96. Kroon, F. P. et al. Restored humoral immune response to influenza vaccination in HIV-infected adults treated with highly active antiretroviral therapy. AIDS 12, F217–F223 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Kruetzmann, S. et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J. Exp. Med. 197, 939–945 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Martin, F. & Kearney, J. F. Marginal-zone B cells. Nature Rev. Immunol 2, 323–335 (2002).

    Article  CAS  Google Scholar 

  99. Bliss, S. J. et al. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect. Dis. 8, 67–80 (2008).

    Article  PubMed  Google Scholar 

  100. Meffre, E. et al. Circulating human B cells that express surrogate light chains and edited receptors. Nature Immunol. 1, 207–213 (2000).

    Article  CAS  Google Scholar 

  101. Sims, G. P. et al. Identification and characterization of circulating human transitional B cells. Blood 105, 4390–4398 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Cuss, A. K. et al. Expansion of functionally immature transitional B cells is associated with human-immunodeficient states characterized by impaired humoral immunity. J. Immunol. 176, 1506–1516 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Anolik, J. H. et al. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis. Rheum. 56, 3044–3056 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Stohl, W. B lymphocyte stimulator protein levels in systemic lupus erythematosus and other diseases. Curr. Rheumatol. Rep. 4, 345–350 (2002).

    Article  PubMed  Google Scholar 

  105. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Charles, E. D. et al. Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia. Blood 111, 1344–1356 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Potter, K. N. et al. Disturbances in peripheral blood B cell subpopulations in autoimmune patients. Lupus 11, 872–877 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Odendahl, M. et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J. Immunol. 165, 5970–5979 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Wehr, C. et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 111, 77–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Wei, C. et al. A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus. J. Immunol. 178, 6624–6633 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 10 Dec 2008 (doi:10.1038./nature07662).

  113. Miller, C. J. et al. Antiviral antibodies are necessary for control of simian immunodeficiency virus replication. J. Virol. 81, 5024–5035 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Gaufin, T. et al. Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain. Blood 23 Jan 2009 (doi:10.1182/blood-2008-09-177741).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Richman, D. D., Wrin, T., Little, S. J. & Petropoulos, C. J. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA 100, 4144–4149 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Mestecky, J. et al. Paucity of antigen-specific IgA responses in sera and external secretions of HIV-type 1-infected individuals. AIDS Res. Hum. Retroviruses 20, 972–988 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Scamurra, R. W. et al. Mucosal plasma cell repertoire during HIV-1 infection. J. Immunol. 169, 4008–4016 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Shattock, R. J., Haynes, B. F., Pulendran, B., Flores, J. & Esparza, J. Improving defences at the portal of HIV entry: mucosal and innate immunity. PLoS Med. 5, e81 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  120. Lopes-Carvalho, T. & Kearney, J. F. Marginal zone B cell physiology and disease. Curr. Dir. Autoimmun. 8, 91–123 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Karlsson Hedestam, G. B. et al. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nature Rev. Microbiol. 6, 143–155 (2008).

    Article  CAS  Google Scholar 

  122. Forster, R. et al. Abnormal expression of the B-cell homing chemokine receptor BLR1 during the progression of acquired immunodeficiency syndrome. Blood 90, 520–525 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. W. Chun, J. Chen and A. Waldner for suggestions on the manuscript and help with the figures. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Author information

Authors and Affiliations

  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Susan Moir & Anthony S. Fauci

Authors
  1. Susan Moir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony S. Fauci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan Moir.

Related links

Related links

FURTHER INFORMATION

Susan Moir and Anthony S. Fauci's homepage

Glossary

Combination antiretroviral therapy

Multi-drug therapy used to suppress viral replication and minimize viral resistance.

Memory B cell

A quiescent antigen-experienced B cell that can rapidly differentiate into a plasma cell on re-exposure to antigen.

Switched or unswitched antibody isotypes

Class switching of the immunoglobulin heavy chain from IgM and IgD to IgG or IgA or IgE allows the diversification of the antibody repertoire, generating antibody isotypes with the same antigen specificity but with different effector functions.

Plasmablast

An antibody-secreting precursor of the non-dividing plasma cell that has the capacity to divide and migrate.

Hypergammaglobulinaemia

Increased levels of immunoglobulin in blood serum.

Idiopathic CD4+ T-cell lymphocytopenia

A disorder of unknown cause that is characterized by decreased CD4+ T-cell counts in the absence of evidence for HIV-1 or HIV-2 infection or any known immunodeficiency or therapy associated with decreased levels of CD4+ T cells.

IgM+ memory B cell

An unswitched CD27+ memory B cell circulating in the peripheral blood that might be related to marginal zone B cells.

Marginal zone B cell

A mature B cell that is enriched anatomically in the marginal zone of the spleen, which is the interface between red pulp and white pulp.

Systemic lupus erythematosus

An autoimmune disease that is characterized by the potential for multiorgan involvement and production of antibodies that are specific for components of the cell nucleus.

Common variable immunodeficiency

A primary immunodeficiency disease with a heterogeneous cause and phenotype that is characterized by hypogammaglobulinaemia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moir, S., Fauci, A. B cells in HIV infection and disease. Nat Rev Immunol 9, 235–245 (2009). https://doi.org/10.1038/nri2524

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2524

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing