Human immunodeficiency virus-1 glycoproteins gp120 and gp160 specifically inhibit the CD3/T cell-antigen receptor phosphoinositide transduction pathway.
The interference of the recombinant HIV-1 glycoproteins gp160 and gp120 with the CD3/T cell antigen receptor (TcR)-mediated activation process has been investigated in the CD4+ diphtheria toxoid-specific human P28D T cell clone. Both glycoproteins clearly inhibit the T cell proliferation induced in an antigen-presenting cell (APC)-free system by various cross-linked monoclonal antibodies specific for the CD3 molecule or the TcR alpha chain (up to 80% inhibition). Biochemical studies further demonstrate that exposure of the T cell clone to both glycoproteins (gps) specifically inhibits the CD3/TcR phospholipase C (PLC) transduction pathway, without affecting the CD3/TcR cell surface expression. Thus, inositol phosphate production, phosphatidic acid turnover, intracellular free calcium, and intracellular pH increase induced by CD3/TcR-specific MAbs are specifically impaired in gps-treated P28D T cells. Addition of purified soluble CD4 prevents binding of gps to T cells and overcomes all observed inhibitions. Maximal inhibitions are obtained for long-term exposure of the T cell clone to gps (16 h). No early effect of gps is observed. By contrast, gp160 and gp120 fail to suppress the CD2-triggered functional and biochemical P28D T cell responses. These results demonstrate that, in addition to their postulated role in the alteration of the interaction between CD4 on T lymphocytes and MHC class II molecules on APC, soluble HIV-1 envelope glycoproteins may directly and specifically impair the CD3/TcR-mediated activation of PLC in uninfected T cells via the CD4 molecule.
Cefai
D
D
Laboratoire d'Immunologie Cellulaire et Tissulaire, Group Hospitalier (GH) Pitié-Salpétrière, Paris, France.
Debre
P
P
Kaczorek
M
M
Idziorek
T
T
Autran
B
B
Bismuth
G
G
D015703:Antigens, CD / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018801:CD2 Antigens; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D002999:Clone Cells; D015686:Gene Products, env / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D010716:Phosphatidylinositols / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D002118:Calcium