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.
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