Innovative CRISPR-Cas9 Strategies for Epigenetic Modulation of HIV-1 Latency: Targeting Tissue-Specific Reservoirs with Multiplexed Approach
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Abstract
The most significant barrier to curing HIV-1 is the persistence of HIV-1 in latent reservoirs, distinct populations of long-lived, transcriptionally silent cells located in blood, lymphoid tissues, gastrointestinal (gut-associated lymphoid tissue), and central nervous system, which necessitate lifelong antiretroviral therapy but reliably fail to result in viral eradication. Maintenance of these reservoirs in an epigenetic state is achieved by DNA methylation, a repressive chromatin remodelling and histone modification and is the mechanism that evades immune detection of the integrated proviruses. Several promising advances are noted herein, such as multiplexed guide RNAs to concurrently target multiple proviral and host regulatory sites; tissue-specific delivery through viral vectors with tissue-specific promoters, ligand-decorated lipid nanoparticles, and exosome delivery; and a concept of integrating combinatorial gene editing with latency reversing agents and broadly neutralizing antibodies to increase immune-mediated eradication. Complimentary preclinical verification procedures such as humanized mouse models and skilled organoids exhibit the security, performance, and versatility of such disciplines. A paradigm shift necessitated by the evidence is a global shift to personalized, reversible epigenetic modelling of latency to overcome heterogeneity and anatomical compartmentalization in the reservoir. In future progress in delivery, specificity, and multi-omic profiling is expected to propel faster clinical translation, not only in HIV-1 but also in other chronic viro-infections, and mark the dawn of a new age of curative genomic medicine.
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