Broadly active zinc finger protein-guided transcriptional activation of HIV

Abstract

Background Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus that causes a persistent viral infection and 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 a means for evasion and long-term persistence. A therapeutic compound that specifically targets and sustainably activates a latent HIV provirus could be transformative and is an overarching goal for the “shock-and-kill” approach to a functional cure for HIV. Results Substantial progress has been made towards the development of recombinant proteins that can target specific genomic loci for gene activation, repression or inactivation by directed mutations. However, most of these modalities are too large, or too complex, for efficient therapeutic application. We describe here the development and testing of a novel recombinant zinc finger protein transactivator, ZFPb-362-VPR, which specifically and potently enhances proviral HIV transcription both in established latency models and across different viral clades. Additionally, ZFP-362-VPR activated HIV reporter gene expression in a well-established primary human CD4+ T-cell latency model and was specific in targeting the HIV LTR as determined from off-target transcriptome analyses. Conclusions: This study provides clear proof of concept for the application of a novel, and therapeutically relevant, protein transactivator to purge cellular reservoirs of HIV-1.

Impact of extracellular vesicles on the pathogenesis, diagnosis, and potential therapy in cardiopulmonary disease

“…Various studies have used EVs as vehicles to target CFTR function. Zinc finger protein activators have been studied as therapeutic tool to activate gene expression (Scott et al, 2021). Stromal-derived MSC were engineered to produce EVs that contain CFTR Zinc Finger Protein fusion with transcriptional activation domains to target CFTR promoter and activate transcription (Villamizar et al, 2021).…”