ABSTRACT
CD19 and CD22 are B lymphocyte cell-surface molecules that positively and negatively regulate antigen receptor signal transduction, respectively. Biochemical studies with B cells from CD19-deficient and CD22-deficient mice indicated that these two regulatory molecules influenced each other's functions: CD22 expression negatively regulated CD19 tyrosine phosphorylation, while optimal CD22 function was dependent on CD19 expression. Functional CD19 and CD22 interactions were also assessed in vivo by generating CD19/CD22 double-deficient mice. Remarkably, the CD19 mutation was dominant to the CD22 mutation in most instances. B lymphocytes from CD19/CD22-deficient and CD19-deficient mice were functionally equivalent despite the negative influence normally provided by CD22 expression. These data collectively suggest that CD19 activates the CD22/SHP1 inhibitory pathway that then acts primarily on CD19.
Subject(s)
Antigens, CD19/physiology , Antigens, CD/physiology , Antigens, Differentiation, B-Lymphocyte/physiology , Cell Adhesion Molecules , Lectins , Receptors, Antigen, B-Cell/physiology , Signal Transduction , Animals , Antibody Formation , Calcium/metabolism , Immunoglobulin M/analysis , Intracellular Signaling Peptides and Proteins , Mice , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Protein Tyrosine Phosphatases/metabolism , Receptors, Antigen, B-Cell/analysis , Sialic Acid Binding Ig-like Lectin 2 , Tyrosine/metabolism , src-Family Kinases/metabolismABSTRACT
Neutralization-escape variants of human immunodeficiency virus type 1 (HIV-1) were sought in persons who had persistent low virus loads and who remained asymptomatic for at least 12-16 years of infection without antiretroviral therapy. Viruses were isolated from 3 persons at two or three time points during the course of infection and were assessed for neutralization by sequential autologous serum samples. Virus neutralization was poor or undetectable with contemporaneous autologous serum but improved with later serum samples for each person. In particular, later isolates resisted neutralization by autologous serum samples that neutralized an earlier isolate. Strain-specific neutralizing antibodies remained detectable for up to 4.2 years without diminishing in titer. The results demonstrate that neutralization-escape variants arise periodically in HIV-1-infected long-term nonprogressors.
