Abstract

HIV persistence within latent reservoirs represents the principal barrier to cure despite lifelong antiretroviral 
therapy (ART). The CCR5 gene encodes a co-receptor essential for HIV-1 entry into CD4⁺ T cells, and individuals 
homozygous for the CCR5-Δ32 mutation exhibit natural resistance to infection. This observation has inspired 
therapeutic strategies to recreate this phenotype through gene editing. This review critically examined the 
translational and clinical evidence on CRISPR-Cas9-mediated CCR5 disruption as a potential functional cure 
strategy in HIV-infected individuals. A structured literature search of PubMed, Scopus, and ClinicalTrials.gov 
(2014–2025) identified peer-reviewed clinical and translational studies investigating CRISPR-Cas9-based CCR5 
gene editing in human subjects living with HIV. CRISPR-Cas9 enables precise CCR5 knockout in autologous 
hematopoietic stem cells (HSCs) and CD4⁺ T cells, generating HIV-resistant progeny following transplantation or 
adoptive transfer. Early clinical trials demonstrated feasibility, with edited cells persisting and reconstituting 
immune function without major toxicity. However, editing efficiency, incomplete reservoir clearance, off-target 
effects, and limited engraftment restrict durable viral remission. Combinatorial approaches integrating latency
reversing agents or dual co-receptor targeting may enhance efficacy. CRISPR-Cas9 CCR5 gene editing offered a 
rational, biologically grounded path toward a functional HIV cure. Yet, translational success demands improved 
delivery systems, refined editing fidelity, and synergistic adjunctive strategies. Future human trials must prioritize 
long-term safety, durable reconstitution of HIV-resistant immunity, and reservoir eradication endpoints.