Abstract

Human immunodeficiency virus (HIV) persists in latent reservoirs despite effective antiretroviral therapy, presenting 
a fundamental barrier to achieving a functional cure. The emergence of clustered regularly interspaced short 
palindromic repeats and CRISPR-associated protein (CRISPR-Cas) systems had revolutionized gene editing 
approaches for HIV eradication strategies. This review examined the current state of CRISPR-Cas technologies 
targeting HIV reservoirs, evaluating molecular mechanisms, therapeutic efficacy, and clinical translation potential. 
A comprehensive literature search was conducted using PubMed, Web of Science, and Embase databases from 2012
2025, focusing on peer-reviewed studies examining CRISPR applications in HIV reservoir targeting, latency 
reversal, and functional cure strategies. Current CRISPR-Cas approaches demonstrated promising results in 
disrupting HIV proviral DNA, with Cas9-mediated excision achieving up to 95% reduction in integrated viral 
sequences in vitro. Multiplex targeting strategies combining CCR5 knockout with proviral excision showed 
enhanced therapeutic potential. Base editing and prime editing technologies offered improved precision for HIV 
genome modification with reduced off-target effects. Clinical translation faced challenges including delivery 
efficiency, off-target mutagenesis, and reservoir heterogeneity. CRISPR-Cas systems represent a transformative 
approach toward HIV functional cure, with ongoing clinical trials demonstrating feasibility and preliminary safety 
profiles. Combination strategies integrating CRISPR with latency-reversing agents and immunotherapy hold 
significant promise for comprehensive reservoir eradication. 
Keywords: CRISPR-Cas, HIV reservoir, Gene editing, Functional cure, Proviral excision.