{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T03:08:59Z","timestamp":1793934539255,"version":"4.8.0"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Human immunodeficiency virus (HIV) infection remains a major global public health challenge. Although highly active antiretroviral therapy (HAART or ART) can effectively control viral replication, it fails to eradicate latent viral reservoirs and poses limitations such as lifelong medication and cumulative drug toxicity. This study focuses on the pivotal role of C-C chemokine receptor 5 (CCR5) gene editing in HIV immunotherapy, particularly highlighting the natural resistance to R5-tropic HIV strains observed in the \u201cBerlin\u201d and \u201cLondon\u201d patients carrying the homozygous CCR5-\u039432 mutation. We further explore the synergistic potential of multiplex gene editing strategies\u2014including CCR5, CXCR4, and HIV LTR loci\u2014and the combinatorial mechanisms between gene editing technologies and immunotherapy. A personalized treatment framework is proposed to address the clinical heterogeneity among people living with HIV. In addition, we assess the balance between long-term safety and global accessibility of gene-editing approaches such as CRISPR\/Cas9, emphasizing strategies to enhance therapeutic efficacy while reducing cost and off-target effects. Our findings suggest that the integration of CCR5-targeted gene editing with immune-based interventions holds great promise for overcoming current therapeutic limitations and achieving functional HIV cure. However, key challenges\u2014such as immune rejection, viral tropism switching, and economic feasibility\u2014must be resolved. This integrative approach provides a robust theoretical and technical foundation for the next generation of HIV treatment paradigms.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1590690","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T02:19:17Z","timestamp":1750213157000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["CCR5 gene editing and HIV immunotherapy: current understandings, challenges, and future directions"],"prefix":"10.3389","volume":"16","author":[{"given":"Jia-Wen","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Jun","family":"Xun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000038768","article-title":"Toward a cure - Advancing HIV\/AIDs treatment modalities beyond antiretroviral therapy: A Review","volume":"103","author":"Alum","year":"2024","journal-title":"Med (Baltimore)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.808068","article-title":"Corrigendum: humanized mice for the evaluation of novel HIV-1 therapies","volume":"12","author":"Abeynaike","year":"2021","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S2055-6640(20)30266-1","article-title":"Maximising the global health impact of future HIV cure-related interventions through advance planning","volume":"4","author":"Brown","year":"2018","journal-title":"J Virus Erad"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00375-19","article-title":"Advances toward curing HIV-1 infection in tissue reservoirs","volume":"94","author":"Henderson","year":"2020","journal-title":"J Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/23744235.2023.2298450","article-title":"Eliminating the HIV tissue reservoir: current strategies and challenges","volume":"56","author":"Li","year":"2024","journal-title":"Infect Dis (Lond)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.112901","article-title":"Immunomodulatory effect of mushrooms and their bioactive compounds in cancer: A comprehensive review","volume":"149","author":"Pathak","year":"2022","journal-title":"BioMed Pharmacother"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00449","article-title":"Long-term delivery of an anti-SIV monoclonal antibody with AAV","volume":"11","author":"Martinez-Navio","year":"2020","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.immuni.2019.02.005","article-title":"Adeno-associated virus delivery of anti-HIV monoclonal antibodies can drive long-term virologic suppression","volume":"50","author":"Martinez-Navio","year":"2019","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI132779","article-title":"In vivo delivery of synthetic DNA-encoded antibodies induces broad HIV-1-neutralizing activity","volume":"130","author":"Wise","year":"2020","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.cytogfr.2017.08.002","article-title":"Immunobiology of the IL-15\/IL-15R\u03b1 complex as an antitumor and antiviral agent","volume":"38","author":"Guo","year":"2017","journal-title":"Cytokine Growth Factor Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2024.1342476","article-title":"Multiple treatment interruptions and protecting HIV-specific CD4 T cells enable durable CD8 T cell response and viral control","volume":"11","author":"Jain","year":"2024","journal-title":"Front Med (Lausanne)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/biom15030378","article-title":"Deep thought on the HIV cured cases: where have we been and what lies ahead","volume":"15","author":"Xiao","year":"2025","journal-title":"Biomolecules"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.virs.2023.01.003","article-title":"Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env(+) cells invivo","volume":"38","author":"Pan","year":"2023","journal-title":"Virol Sin"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.06.022","article-title":"Ready for repair? 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