“Targeting host signaling pathways for inhibiting HIV replication”

HIV‐1 utilizes host cell pathways to replication and generate new virus and productive infection of T cells requires T cell activation and actin cytoskeletal reorganization. We have explored the cellular signaling pathways used by this virus with the goal of targeting them to inhibiting viral replication. We show that HIV‐1 utilizes the T cell receptor (TCR) and CD28 costimulatory pathways to enhance viral transcription. TCR/CD28 activation of T cells results in enhanced activation of HIV‐1 proviral transcription via tyrosine phosphorylation of the GEF Vav and activation and binding of NF‐¿B to the HIV‐ 1 long terminal repeat. We also show that the tyrosine kinase ITK is activated by the TCR/CD28 signaling pathway, as well as the viral co‐receptor CXCR4. ITK modulates the Vav signaling pathway and regulates TCR and CXCR4 induced cytoskeletal rearrangements. We show that targeting ITK via siRNA, an ITK selective inhibitor, or using a dominant negative ITK leads to reduction in p24 levels after HIV‐1 infection. Targeting ITK after HIV‐1 infection has been established leads to a decrease in virus replication and spread. This was due to a block in several steps in the viral life cycle, viral entry due to reduced actin rearrangement, and blocks in viral transcription and viral particle formation. Our data suggest that targeting host signaling machinery may be an effective approach to targeting HIV‐1, reducing the options for the escape of viral mutants.