HIV type 1 envelope glycoprotein 120 carboxy-terminal peptide-induced human T cell lines selectively suppress heterogeneous proliferative T cell responses to soluble antigens.
It has been proposed that the highly conserved human immunodeficiency virus type 1 (HIV-1) envelope gp120 carboxy-terminal sequence, TKAKRRVVEREKR (CT120), may represent a functional mimic of the human leukocyte antigen (HLA) class II DR beta-chain third hypervariable region (HVR3) sequence motif located at position 69-81. Presentation of this potentially pathogenic fragment by HLA class I and/or II molecules, in a manner analogous to the indirect pathway of allorecognition, may induce both widespread cellular activation and also break self-tolerance, resulting in the selective and progressive anti-self HLA class II-directed immune suppression, which is a central feature of HIV-1 infection and the associated acquired immune deficiency syndrome (AIDS). To investigate the functional role of the HIV-1 gp120 C-terminal fragment T cell lines (TCLs) were raised from three healthy HIV-1-seronegative subjects at low risk of HIV-1 exposure, by repeated stimulation with a short synthetic 13-mer CT120 peptide in vitro. Graded concentrations (10[3] to 5 x 10[4]) of CT120 TCLs suppressed the primary 6-day proliferation of autologous PBMCs in response to the soluble antigens tetanus toxoid (TT) and purified protein derivative (PPD). In contrast, CT120 TCLs demonstrated no suppressive effect on 3-day phytohemagglutinin (PHA), concanavalin A (ConA), and pokeweed mitogen (PWM) mitogenic responses. Fractionation of CT120 TCLs into highly purified CD4+ and CD8+ T cell subsets demonstrated that the CD8+ T cell fraction mediated the suppressor effector function. HLA restriction analysis revealed a complex pattern as both anti-HLA class II DR and anti-HLA class I (A, B, C) MAbs inhibited proliferation of oligoclonal CD8+ CT120 TCLs. Strategies aimed at specifically inhibiting such putative immunopathogenic HIV-1-encoded T cell epitopes may be an important consideration for development of future HIV-1 immunotherapy.
Wilson
S E
SE
Academic Virology, The London Hospital Medical College, UK. swilson@hivnet.fhcrc.org
Habeshaw
J A
JA
Addawe
M A
MA
Hounsell
E F
EF
Oxford
J S
JS
D000328:Adult; D000595:Amino Acid Sequence; D019138:Antibodies, Blocking / Q000276:immunology; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D002478:Cells, Cultured; D003208:Concanavalin A / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D018023:HIV Seronegativity; D015497:HIV-1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007108:Immune Tolerance; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology*; D010835:Phytohemagglutinins / Q000276:immunology; D011043:Pokeweed Mitogens / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology; D014373:Tuberculin / Q000276:immunology
D019138:Antibodies, Blocking; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D010835:Phytohemagglutinins; D011043:Pokeweed Mitogens; D013745:Tetanus Toxoid; D014373:Tuberculin; D003208:Concanavalin A