Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease.

HIV disease is associated with abnormalities in all major lymphocyte populations, including B cells. Aberrancies in the B-cell compartment can be divided into 3 broad categories: changes that arise as a result of HIV-induced immune activation, changes that arise as a result of HIV-induced lymphopenia, and changes that arise independently of these 2 parameters. We review recent developments in all 3 categories of abnormalities and highlight how observations made in the early years of the HIV epidemic are better understood today in large part because of the advent of effective antiretroviral therapy. Insight into the mechanisms of B-cell dysfunction in HIV disease has also been achieved as a result of increased knowledge of the B-cell subpopulations as they exist in healthy individuals, compared with their abnormalities in HIV-infected individuals. A better understanding of the pathogenic mechanisms of B-cell abnormalities in HIV disease can potentially lead to new strategies for improving antibody responses against opportunistic pathogens that afflict HIV-infected individuals and against HIV itself, in the context of both HIV infection and an antibody-based HIV vaccine.

[1]  K. Rajewsky,et al.  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 , 1998, The Journal of experimental medicine.

[2]  P. Brandtzaeg,et al.  Intestinal B cell hyperactivity in AIDS is controlled by highly active antiretroviral therapy , 2004, Gut.

[3]  F Miedema,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). , 2000, Blood.

[4]  D. Follmann,et al.  Compromised B cell responses to influenza vaccination in HIV-infected individuals. , 2005, The Journal of infectious diseases.

[5]  T. Chun,et al.  Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms , 2006, Proceedings of the National Academy of Sciences.

[6]  J. Hayashi,et al.  Downregulation of CXCR5 in CD27− B cells of HIV‐1 infected patients , 2004, Journal of medical virology.

[7]  Adeeba Kamarulzaman,et al.  AIDS Res Hum Retroviruses , 2006 .

[8]  J. McCune,et al.  The dynamics of CD4+ T-cell depletion in HIV disease , 2001, Nature.

[9]  J. Sodroski,et al.  Immunoglobulin V(H) usage during primary infection of rhesus monkeys with chimeric simian-human immunodeficiency viruses , 1997, Journal of virology.

[10]  O. Pickeral,et al.  Decreased Survival of B Cells of HIV-viremic Patients Mediated by Altered Expression of Receptors of the TNF Superfamily , 2004, The Journal of experimental medicine.

[11]  A. Fauci,et al.  Brief Report Results and Discussion , 2022 .

[12]  T. Chun,et al.  Deleterious Effect of HIV-1 Plasma Viremia on B Cell Costimulatory Function , 2003, The Journal of Immunology.

[13]  R. Siegel.  Caspases at the crossroads of immune-cell life and death , 2006, Nature Reviews Immunology.

[14]  T. Kipps,et al.  Immunoglobulin VH3 gene products: natural ligands for HIV gp120. , 1993, Science.

[15]  S. Tangye,et al.  Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage , 2005, The Journal of Immunology.

[16]  Anthony S Fauci,et al.  An HIV vaccine--evolving concepts. , 2007, The New England journal of medicine.

[17]  K. O'Brien,et al.  The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. , 2008, The Lancet. Infectious diseases.

[18]  S. Wahl,et al.  Impact of HIV-1 Infection on VH3 Gene Repertoire of Naive Human B Cells1 , 2000, The Journal of Immunology.

[19]  D. Nickle,et al.  Human Immunodeficiency Virus Type 1 Bound to B Cells: Relationship to Virus Replicating in CD4+ T Cells and Circulating in Plasma , 2002, Journal of Virology.

[20]  E. Ruiz-Mateos,et al.  Effect of Hepatitis C Virus Coinfection on Humoral Immune Alterations in Naïve HIV-Infected Adults on HAART: A Three Year Follow-Up Study , 2005, Journal of Clinical Immunology.

[21]  L. Lopalco,et al.  Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. , 2006, Blood.

[22]  S. Kashiwagi,et al.  Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug-naive and HAART-treated HIV type 1-infected patients. , 2004, AIDS research and human retroviruses.

[23]  V. Ng.  B-lymphocytes and autoantibody profiles in HIV disease , 1996, Clinical Reviews in Allergy and Immunology.

[24]  F. Chiodi,et al.  Loss of memory (CD27) B lymphocytes in HIV-1 infection , 2001, AIDS.

[25]  R. Rickert.  Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. , 2005, Current opinion in immunology.

[26]  K. Luzuriaga,et al.  Immunogenicity and efficacy of childhood vaccines in HIV-1-infected children. , 2004, The Lancet. Infectious diseases.

[27]  N. Letvin.  Progress and obstacles in the development of an AIDS vaccine , 2006, Nature Reviews Immunology.

[28]  J. Lindsey,et al.  Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. , 2001, The Pediatric infectious disease journal.

[29]  Mauro Vaccarezza,et al.  Role of Lymphoid Organs in the Pathogenesis of Human Immunodeficiency Virus (HIV) Infection , 1994, Immunological reviews.

[30]  T. Chun,et al.  HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Alan S. Perelson,et al.  Turnover of CD4+ and CD8+ T Lymphocytes in HIV-1 Infection as Measured by Ki-67 Antigen , 1998, The Journal of experimental medicine.

[32]  R. Grant,et al.  Increased production of IL-7 accompanies HIV-1–mediated T-cell depletion: implications for T-cell homeostasis , 2001, Nature Medicine.

[33]  Q. Sattentau,et al.  Antibody-Based HIV-1 Vaccines: Recent Developments and Future Directions , 2007, PLoS medicine.

[34]  Tao Dong,et al.  Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection , 2004, PLoS biology.

[35]  M. Hatherill.  Sepsis predisposition in children with human immunodeficiency virus , 2005, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[36]  F. van Leth,et al.  Epstein-Barr virus infects B and non-B lymphocytes in HIV-1-infected children and adolescents. , 2006, The Journal of infectious diseases.

[37]  A. Fauci,et al.  Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. , 1983, The New England journal of medicine.

[38]  A S Perelson,et al.  Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. , 1998, Science.

[39]  A. Komiyama,et al.  Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. , 2001, Clinical immunology.

[40]  Mark Connors,et al.  Broad HIV-1 neutralization mediated by CD4-binding site antibodies , 2007, Nature Medicine.

[41]  M. Lederman,et al.  A potential role for interleukin-7 in T-cell homeostasis. , 2001, Blood.

[42]  Wei Wang,et al.  Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals , 2008, The Journal of experimental medicine.

[43]  Kirk A Easley,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. , 2000, The Journal of allergy and clinical immunology.

[44]  D. Ho,et al.  HIV-1 Antigen–specific and –nonspecific B Cell Responses Are Sensitive to Combination Antiretroviral Therapy , 1998, The Journal of experimental medicine.

[45]  J. Sodroski,et al.  The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus , 2008, Nature Reviews Microbiology.

[46]  R. Lempicki,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. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Dierich,et al.  Role of complement in the control of HIV dynamics and pathogenesis. , 2003, Vaccine.

[48]  A. Fauci,et al.  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. , 1995, Journal of immunology.

[49]  A. Fauci,et al.  NK cells in HIV infection: Paradigm for protection or targets for ambush , 2005, Nature Reviews Immunology.

[50]  M. Tomayko,et al.  Intrinsic properties of human and murine memory B cells , 2006, Immunological reviews.

[51]  B. Williams,et al.  Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  J. Margolick,et al.  Failure of T-cell homeostasis preceding AIDS in HIV-1 infection , 1995, Nature Medicine.

[53]  P. Lipsky,et al.  Identification and characterization of circulating human transitional B cells. , 2005, Blood.

[54]  Tahir A. Rizvi,et al.  Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian–human immunodeficiency virus infection , 2000, Nature Medicine.

[55]  Thomas Boehm,et al.  Human Immunoglobulin M Memory B Cells Controlling Streptococcus pneumoniae Infections Are Generated in the Spleen , 2003, The Journal of experimental medicine.

[56]  L. D'Orsogna,et al.  Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy , 2007, AIDS.

[57]  T. Chun,et al.  B Cells of HIV-1–Infected Patients Bind Virions through Cd21–Complement Interactions and Transmit Infectious Virus to Activated T Cells , 2000, The Journal of experimental medicine.

[58]  L. Lopalco,et al.  Primary HIV-1 Infection Sets the Stage for Important B Lymphocyte Dysfunctions , 2005, Retrovirology.

[59]  J. Goudsmit,et al.  Potent antiretroviral therapy initiates normalization of hypergammaglobulinemia and a decline in HIV type 1-specific antibody responses. , 2001, AIDS research and human retroviruses.

[60]  B. Gazzard,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 Disease1 , 2007, The Journal of Immunology.

[61]  Alan S. Perelson,et al.  Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques1 , 2003, The Journal of Immunology.

[62]  O. Martínez-Maza,et al.  B-cell activation and lymphoma in patients with HIV , 2002, Current opinion in oncology.

[63]  J. Cöster,et al.  Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection. , 1997, AIDS research and human retroviruses.

[64]  Richard A. Lempicki,et al.  Identification of Dynamically Distinct Subpopulations of T Lymphocytes That Are Differentially Affected by HIV , 2001, The Journal of experimental medicine.

[65]  M. Dietrich,et al.  Lymphatic tissue changes in AIDS and other retrovirus infections: tools and insights. , 1990, Lymphology.

[66]  A. Milito.  B lymphocyte dysfunctions in HIV infection. , 2004 .

[67]  Jeffrey N. Martin,et al.  Effect of Long‐Term Highly Active Antiretroviral Therapy in Restoring HIV‐Induced Abnormal B‐Lymphocyte Function , 2002, Journal of acquired immune deficiency syndromes.

[68]  Jun Li,et al.  Antiviral Antibodies Are Necessary for Control of Simian Immunodeficiency Virus Replication , 2007, Journal of Virology.

[69]  Andreas Radbruch,et al.  Antibodies and B cell memory in viral immunity. , 2007, Immunity.

[70]  M. Cooper,et al.  Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells , 2005, The Journal of experimental medicine.

[71]  G. Freeman,et al.  The B7 family revisited. , 2005, Annual review of immunology.

[72]  T. Kuijpers,et al.  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 , 2006, Pediatrics.

[73]  T. Chun,et al.  Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: Correlation with increased IL-7 , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[74]  M. Proschan,et al.  Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. , 2008, The Journal of infectious diseases.

[75]  P. Lambin,et al.  Selective alterations of the antibody response to HIV-1 , 1998, Applied biochemistry and biotechnology.

[76]  B. Williams,et al.  Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays , 1998 .

[77]  D. Klinman,et al.  Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. , 1992, The Journal of clinical investigation.

[78]  S. Tangye,et al.  Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity1 , 2006, The Journal of Immunology.

[79]  Martin Meier-Schellersheim,et al.  Pathogenesis of HIV infection: what the virus spares is as important as what it destroys , 2006, Nature Medicine.

[80]  J. Mascola,et al.  Protection of Macaques against Pathogenic Simian/Human Immunodeficiency Virus 89.6PD by Passive Transfer of Neutralizing Antibodies , 1999, Journal of Virology.

[81]  T. Chun,et al.  Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[82]  M. Zembala,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. , 2002, Clinical immunology.