Many mechanisms have been proposed for uninfected, bystander CD4 T cell depletion, such as direct action of HIV proteins, activation induced cell death, autologous cell mediated cytotoxicity against un infected T cells, and dysregulation of cytokine chemo kine production. Several of those mechanisms implicate HIV envelope glycoprotein as a professional moter of uninfected CD4 T cell depletion. We wished to know the effects of CCR5 tropic HIV Env signal transduction via CD4 or CCR5. Typically, these signaling receptors are involved in controlling immune responses. Env binding will even set off signal transduction and may perhaps have an effect on HIV infec tion and virus replication. In fact, when R5 tropic Env glycoprotein binds CCR5 on CD4 negative T cells, p38 MAP kinase is activated, caspase action increased and Fas independent cell death resulted.
It was also reported that HIV Env glycoprotein induced apoptosis of uninfected, CD4 damaging neurons, cardiomyocytes, hepatocytes, proximal renal tubu lar cells, lung endothelial cells and human vascular endothelial cells. The mechanisms selleckchem for Env induced cell death are contro versial. Early research proposed that oligomeric or particle associated Env cross hyperlinks CD4 which in creases spontaneous cell apoptosis, activation induced cell death and cell susceptibility to Fas dependent apoptosis. Others argued towards a direct function for CD4 from the pathway for cell death. It had been reported that Env induced apoptosis only in T cell lines lac king a CD4 cytoplasmic domain and Env mu tants that bind CXCR4 but don’t bind CD4, even now induced apoptosis in comparison to mutants defective for CXCR4 binding that didn’t cause cell death. Env dependent CD4 T cell death was blocked by CCR5 or CXCR4 binding antagonists and soluble CD4 improved R5 or X4 induced CD4 T cell death.
Our studies focused on signal transduction events driven by HIV Env binding to cell surface receptors on tonsil CD4 T cells. We’re defining discrete signaling events just after CD4 or CCR5 binding, and studying cross regulation between these pathways to understand far more in regards to the function of each important HIV receptor past their established roles in virus penetration. Receptor informative post signaling may very well be involved in both indirect cell death plus the con trol of productive infection. By focusing on protein kinases associated with signal transduction, applying compact molecule in hibitory medicines previously in clinical improvement for cancer treatment, we may well determine new targets for antiretroviral agents amid host cell pathways. Results HIV R5 tropic Env induces tonsil CD4 T cell death We initial tested if HIV R5 tropic Env kills human tonsil CD4 T cells. Fresh, CD4 T cells were purified by ne gative selection from dissected human tonsils.