The CD4 molecule functions as a co-receptor for antigen recognition and subsequent activation of T lymphocytes reactive with antigen presented by MHC class II molecules. The CD4 molecule is also the receptor for the T- lymphotropic HIV-1 virus and binds the envelope glycoprotein gp120 with high affinity. In patients with AIDS the number of CD$+ T cells is significantly reduced by viral induced cytopathicity of HIV-1 infected cells. There is also evidence suggesting that the binding of free gp120 by CD4 may be primarily responsible for death in vivo of uninfected cells. Already much is known about the fine structure of this CD4-gp120 interaction and this knowledge has aided the design of either gp120- or CD4-based vaccines or immunoadhesins. In the evaluation of such products as vaccines, their effect on naive T cells or APC must also be determined. This application seeks to define the role of CD$ in T cell activation and examine the effect that gp120 has on these functions. Although in many systems CD4-mediated T cell activation is achieved by the addition of antibodies to CD4, in order to study a system which may be more biologically relevant we will concentrate on activation induced by the normal ligand (i.e., MHC class II molecules). Our approach is to perform oligonucleotide directed mutagenesis of MHC class II genes to define mutant molecules which lack the epitope recognized by CD4 but still retain the ability to present antigen to the TcR. Using antigen presenting cells which express either wild type or mutant class II molecules which lack the epitope recognized by CD4, the biochemical and physiological role of the CD4-MHC Class II interaction within particular T cell clones or hybridomas can be determined. This system will also provide us with an ideal opportunity to examine the direct effects of gp120 binding on the CD4/class II interaction in CD4+ T cells which are either dependent or independent on CD4 for their reactivity.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Takase, K; Kelleher, C A; Terada, N et al. (1996) Dissociation of EBV genome replication and host cell proliferation in anti-IgG-stimulated Akata cells. Clin Immunol Immunopathol 81:168-74
Kelleher, C A; Wilkinson, D A; Freeman, J D et al. (1996) Expression of novel-transposon-containing mRNAs in human T cells. J Gen Virol 77 ( Pt 5):1101-10
Cotton, M F; Cassella, C; Rapaport, E L et al. (1996) Apoptosis in HIV-1 Infection. Behring Inst Mitt :220-31
Dreyfus, D H; Kelleher, C A; Jones, J F et al. (1996) Epstein-Barr virus infection of T cells: implications for altered T-lymphocyte activation, repertoire development and autoimmunity. Immunol Rev 152:89-110
Lucas, J J; Szepesi, A; Domenico, J et al. (1995) Differential regulation of the synthesis and activity of the major cyclin-dependent kinases, p34cdc2, p33cdk2, and p34cdk4, during cell cycle entry and progression in normal human T lymphocytes. J Cell Physiol 165:406-16
Kelleher, C A; Paterson, R K; Dreyfus, D H et al. (1995) Epstein-Barr virus replicative gene transcription during de novo infection of human thymocytes: simultaneous early expression of BZLF-1 and its repressor RAZ. Virology 208:685-95
Terada, N; Takase, K; Papst, P et al. (1995) Rapamycin inhibits ribosomal protein synthesis and induces G1 prolongation in mitogen-activated T lymphocytes. J Immunol 155:3418-26
Drevets, D A; Elliott, A M (1995) Fluorescence labeling of bacteria for studies of intracellular pathogenesis. J Immunol Methods 187:69-79
Lucas, J J; Szepesi, A; Domenico, J et al. (1995) Effects of iron-depletion on cell cycle progression in normal human T lymphocytes: selective inhibition of the appearance of the cyclin A-associated component of the p33cdk2 kinase. Blood 86:2268-80
Campbell, K S; Bedzyk, W D; Cambier, J C (1995) Manipulation of B cell antigen receptor tyrosine phosphorylation using aluminum fluoride and sodium orthovanadate. Mol Immunol 32:1283-94

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