Project Summary Targeted transcriptional activation of HIV Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus that causes a persistent viral infection that results in the demise of immune regulatory cells. Clearance of HIV-1 infection by the immune system is inefficient, and integration of proviral DNA into the genome of host cells provides an efficient means for evasion and long-term persistence. This proviral integrant is potentially subjected to the regulatory control which ultimately leads to the orchestration of transcriptional shutdown and a latent state in resting CD4+ cells (reviewed in (1)). Viral latency is thought to be the result of the virus remaining quiescent and undetected in resting CD4+ T-cells (2). A methodology to reactivate latent virus is paramount to developing afunctional cure and purging reservoirs of viral infected T-cells. We have recently developed three recombinant proteins that can activate HIV directly or T-cells harboring latent provirus. We propose here to develop three aims to develop an HIV specific and general T-cell transcriptional activator to be used to purge reservoirs of latent virus, with the premise that it is possible to activate, and purge HIV from infected ART induced latent infected T-cells in vivo. In Aim 1, we will develop and contrast recombinant protein, exosome, or lipid nanoparticle delivered ZFP- 362-VPR for transcriptional activation of latent HIV while in Aim 2 we will we will Develop and test recombinant CD18 and truncated CD11b I-domain A proteins for targeted activation of HIV in ART induced latently infected CD4+ T-cells. AIM 3 will contrast ZFP-362-VPR, recombinant CD18, and truncated CD11b I-domain A in vivo for targeted activation of latent HIV. These Aims are designed to be complimentary used in conjunction with one another to stably activate and potentially purge HIV- 1 provirus from latently infected cells.