The experiments proposes to analyze the signal transduction pathway induced in T cells by the binding of HIV to CD4 receptors. In preliminary studies the investigator has shown that HIV or gp120 binding induced the association and activation of lck and raf-1 kinases. Binding did not induce ras activation or ras association with raf-1, thereby disassociating HIV pathways from one of the classical activation pathways. This proposal addresses the hypothesis that activation of this pathway is an important component of early gene activation which enhances HIV replication. The proposed studies will investigate this novel activation scheme through: (1) analysis of the lck/raf-1 pathway in CD4 cells of rapid and LTNP; (2) investigation of the impact of suppression of the lck/raf-1 pathway on nuclear transcription, using dominant negative and ribozyme approaches within raf-1 and ras; and (3) definition of the raf-1 binding domain that interacts with lck, and the importance of lck/raf-1 association in HIV replication.
|Popik, W; Pitha, P M (2000) Inhibition of CD3/CD28-mediated activation of the MEK/ERK signaling pathway represses replication of X4 but not R5 human immunodeficiency virus type 1 in peripheral blood CD4(+) T lymphocytes. J Virol 74:2558-66|
|Popik, W; Hesselgesser, J E; Pitha, P M (1998) Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway. J Virol 72:6406-13|
|Popik, W; Pitha, P M (1998) Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 Virology 252:210-7|