Cyclosporin A sensitivity of the HIV-1 long terminal repeat identifies distinct p56lck-dependent pathways activated by CD4 triggering.
The CD4 co-receptor interacts with nonpolymorphic regions of major histocompatibility complex class II molecules on antigen-presenting cells. This interaction results in the mobilization of a number of signaling mediators shared by the T cell receptor (TcR) signaling pathway and thus amplifies TcR-generated signals. We have investigated the outcome of CD4 engagement on the activation of both cellular transcription factors and the HIV-1 long terminal repeat (LTR). We show that CD4 triggering activates different pathways of HIV LTR activation which can be identified by their sensitivity to the immunosuppressant cyclosporin A. The response of the inducible cellular transcription factors involved in HIVLTR activation shows that both nuclear factor (NF)-kappa B and NF-AT mediate a cyclosporin A-sensitive response to CD4, while AP-1 is at least in part responsible for the cyclosporin A-insensitive response. Both pathways can, however, be blocked by a kinase-defective dominant negative p56lck mutant, supporting an essential role for p56lck kinase activity in CD4-dependent signal transduction. A functional analysis of different CD4 epitopes using either anti-CD4 mAb or HIV-1 gp120 reveals a common epitope-specific activation of both the LTR and of the transcription factors NF-kappa B and NF-AT.
Di Somma
M M
MM
Department of Evolutionary Biology, University of Siena, Italy.
Majolini
M B
MB
Burastero
S E
SE
Telford
J L
JL
Baldari
C T
CT
D001323:Autoantibodies / Q000502:physiology; D015704:CD4 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000939:Epitopes; D016325:HIV Long Terminal Repeat; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
D001323:Autoantibodies; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D000939:Epitopes; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases