Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection.
Hypergammaglobulinemia and defective humoral immunity are hallmarks of HIV-1 infection. Naive B cells have been recently suggested as the major source of hypergammaglobulinemia in chronic viral infections. We recently reported that HIV-1-infected patients carry low levels of memory B cells. Here we studied whether defects in the naive and memory B cells in HIV-1-infected patients translated into hypergammaglobulinemia and defective humoral immunity against specific antigens. Naive B cells from HIV-1-infected patients exhibited abnormal expression of the activation/differentiation markers CD70 and leukocyte-associated Ig-like receptor (LAIR-1). Activated naive B cells from patients showed a significant increase in the intracellular immunoglobulin G (IgG) content ex vivo and this activated phenotype correlated to hypergammaglobulinemia and to the ability of naive B cells from patients to secrete IgG in vitro. We analyzed the levels of antibodies to tetanus toxoid, measles, and HIV-1 in relation to memory B cells and observed a significant reduction of antigen-specific antibodies in patients with low-memory B lymphocytes. Nevertheless, hypergammaglobulinemia and levels of polyspecific self-reactive antibodies were comparable in patients with normal and low memory B cells. We conclude that reduction of memory B lymphocytes in HIV-1 infection correlates with defective humoral immunity and that hyperactivated naive B cells may represent the source of abnormal IgG production in HIV-1 infection. Our results may be relevant to the design of HIV-1 therapeutical vaccines and to the clinical management of HIV-1-infected patients.
De Milito
Angelo
A
Microbiology and Tumor Biology Center, Karolinska Institute, and Gay Men's Health Clinic, The Soder Hospital, Stockholm, Sweden. angelo.de.milito@mtc.ki.se
Nilsson
Anna
A
Titanji
Kehmia
K
Thorstensson
Rigmor
R
Reizenstein
Elisabet
E
Narita
Mitsuo
M
Grutzmeier
Sven
S
Sönnerborg
Anders
A
Chiodi
Francesca
F
D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002450:Cell Communication / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000150:complications* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006942:Hypergammaglobulinemia / Q000276:immunology* / Q000821:virology*; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping; D008297:Male; D008457:Measles / Q000276:immunology; D008875:Middle Aged; D013745:Tetanus Toxoid / Q000276:immunology
D000914:Antibodies, Viral; D015483:HIV Antibodies; D007074:Immunoglobulin G; D013745:Tetanus Toxoid