CRISPR-Cas Gene Editing Approaches for HIV Reservoir Elimination and Functional Cure Strategies

Background: Human immunodeficiency virus (HIV) infection remains a global health challenge, with more than 38 million individuals living with the virus worldwide in 2023. Despite antiretroviral therapy (ART) effectively suppressing viral replication, latent reservoirs of integrated proviral DNA prevent eradication and necessitate lifelong treatment. Purpose: This review examined CRISPR-Cas gene editing technologies as promising strategies for eliminating latent HIV reservoirs and achieving functional cure outcomes. Methodology: This review synthesized peer-reviewed studies from PubMed, Web of Science, and Scopus (2015–2025), focusing on in vitro, in vivo, and preclinical reports that evaluate CRISPR-Cas applications against HIV latency and persistence. Findings: CRISPR-Cas9 and next-generation Cas systems have demonstrated efficient cleavage of proviral DNA, excision of integrated genomes, and disruption of essential viral genes. In preclinical studies, Cas9-guided strategies achieved up to 90% reduction of integrated HIV DNA in latently infected cells. Emerging innovations included base and prime editing for precise nucleotide modifications, multiplex targeting to prevent viral escape, and delivery systems using adeno-associated virus (AAV) and lipid nanoparticles. Combination strategies that pair CRISPR editing with latency-reversing agents (LRAs) or immune-enhancing modalities have shown synergistic effects in clearing reservoirs in animal models. CRISPR-Cas gene editing provided a rational and increasingly feasible approach to functional HIV cure strategies. Key challenges remained in delivery specificity, off-target effects, and immune safety. Translational progress will require carefully designed clinical trials integrating CRISPR with existing and novel therapeutic paradigms. Keywords: CRISPR-Cas, HIV reservoirs, Functional cure, Gene editing, Latency.