Abstract

Human immunodeficiency virus type 1 persisted as a global health challenge affecting approximately 39 million 
individuals worldwide, with current antiretroviral therapy requiring lifelong adherence while failing to eliminate 
latent viral reservoirs. CRISPR-Cas9 represented a revolutionary gene editing technology capable of precise 
genomic modifications, offering unprecedented opportunities to disrupt integrated proviral DNA and confer 
resistance to viral entry through targeted modification of host cellular factors. This review critically examined the 
application of CRISPR-Cas9 gene editing systems toward achieving functional cure or eradication of human 
immunodeficiency virus infection, evaluating molecular strategies, preclinical evidence, clinical translation efforts, 
and obstacles limiting therapeutic implementation. A comprehensive synthesis of mechanistic studies, preclinical 
models, early phase clinical trials, and theoretical frameworks published through early 2025 addressing CRISPR
Cas9 targeting of integrated provirus, CCR5 coreceptor modification, and combinatorial approaches was utilized in 
writing this review. CRISPR-Cas9 systems demonstrated capacity to excise integrated proviral sequences from 
infected cell genomes, disrupt CCR5 coreceptor expression to prevent viral entry, and target conserved viral 
regulatory elements across diverse human immunodeficiency virus subtypes in cellular and animal models. However, 
substantial barriers persisted including incomplete elimination of latent reservoirs, off target genomic modifications, 
inefficient delivery to anatomical sanctuary sites, immune responses against Cas9 protein, viral escape through 
sequence variation, and technical challenges in achieving therapeutically relevant editing frequencies in vivo. While 
CRISPR-Cas9 technologies offered compelling theoretical frameworks for human immunodeficiency virus cure, 
translation from preclinical promise to clinical reality required innovations in delivery systems, editing efficiency, 
safety profiles, and strategies addressing viral reservoir heterogeneity.