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Cells containing active provirus express viral proteins and have been successfully targeted using broadly neutralizing antibodies (bnAbs). In contrast, cells containing latent provirus cannot be specifically targeted without latency reactivation. Meaningful depletion of the latent HIV or simian immunodeficiency virus (SIV) reservoirs has not been demonstrated except with cytotoxic conditioning for bone-marrow transplantation. Here we show that both the active and latent SIV reservoirs can be eliminated from infant macaques via profound but transient depletion of cells that express CCR5 using a single shot of CCR5\/CD3 bispecific antibody. Neonatal rhesus macaques were infected with SIVmac251, then treated with ART beginning at 1\u2009week after infection, followed by treatment with either a CCR5\/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and accelerated the decline in plasma viraemia. Upon ART cessation, while rebound occurred quickly in all animals treated with ART alone, most animals treated with CCR5\/CD3 bispecific antibody remained aviraemic for &gt;3\u2009months. Several remained aviraemic to the end of follow-up and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment achieves meaningful depletion of the replication-competent SIV reservoir and supports the possibility that clinically meaningful depletion of the HIV reservoir might be achievable for recently infected individuals.<\/jats:p>","DOI":"10.1038\/s41564-026-02511-3","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T09:03:30Z","timestamp":1792400610000},"page":"3102-3114","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SIV reservoir depletion and clearance from neonatal macaques following transient CCR5 depletion"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2539-0338","authenticated-orcid":false,"given":"Jesse D.","family":"Deere","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1350-3056","authenticated-orcid":false,"given":"David","family":"Merriam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kawthar","family":"Machmach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1258-7369","authenticated-orcid":false,"given":"W. 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Long-term control of HIV by CCR5 Delta32\/Delta32 stem-cell transplantation. N. Engl. J. Med. 360, 692\u2013698 https:\/\/doi.org\/10.1056\/NEJMoa0802905 (2009).","DOI":"10.1056\/NEJMoa0802905"},{"key":"2511_CR2","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1097\/QAD.0b013e328340fe28","volume":"25","author":"G Hutter","year":"2011","unstructured":"Hutter, G. & Thiel, E. Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: an update after 3 years and the search for patient no. 2. AIDS 25, 273\u2013274 https:\/\/doi.org\/10.1097\/QAD.0b013e328340fe28 (2011).","journal-title":"AIDS"},{"key":"2511_CR3","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/s41586-019-1027-4","volume":"568","author":"RK Gupta","year":"2019","unstructured":"Gupta, R. K. et al. HIV-1 remission following CCR5\u039432\/\u039432 haematopoietic stem-cell transplantation. Nature 568, 244\u2013248 https:\/\/doi.org\/10.1038\/s41586-019-1027-4 (2019).","journal-title":"Nature"},{"key":"2511_CR4","doi-asserted-by":"publisher","first-page":"e340","DOI":"10.1016\/S2352-3018(20)30069-2","volume":"7","author":"RK Gupta","year":"2020","unstructured":"Gupta, R. K. et al. Evidence for HIV-1 cure after CCR5\u039432\/\u039432 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. Lancet HIV 7, e340\u2013e347 https:\/\/doi.org\/10.1016\/S2352-3018(20)30069-2 (2020).","journal-title":"Lancet HIV"},{"key":"2511_CR5","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/J.CELL.2023.02.030","volume":"186","author":"J Hsu","year":"2023","unstructured":"Hsu, J. et al. HIV-1 remission and possible cure in a woman after haplo-cord blood transplant. Cell 186, 1115\u20131126.e8 https:\/\/doi.org\/10.1016\/J.CELL.2023.02.030 (2023).","journal-title":"Cell"},{"key":"2511_CR6","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/S41591-023-02213-X","volume":"29","author":"BEO Jensen","year":"2023","unstructured":"Jensen, B. E. O. et al. In-depth virological and immunological characterization of HIV-1 cure after CCR5\u039432\/\u039432 allogeneic hematopoietic stem cell transplantation. Nat. Med. 29, 583\u2013587 https:\/\/doi.org\/10.1038\/S41591-023-02213-X (2023).","journal-title":"Nat. Med."},{"key":"2511_CR7","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1056\/NEJMc2312556","volume":"390","author":"J Dickter","year":"2024","unstructured":"Dickter, J. et al. HIV-1 remission after allogeneic hematopoietic-cell transplantation. N. Engl. J. Med. 390, 1125\u20131131 https:\/\/doi.org\/10.1056\/NEJMc2312556 (2024).","journal-title":"N. Engl. J. 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E. et al. Seroconversion following nonoccupational postexposure prophylaxis against HIV. Clin. Infect. Dis. 41, 1507\u20131513 (2005).","journal-title":"Clin. Infect. Dis."},{"key":"2511_CR11","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1586\/eri.11.20","volume":"9","author":"D Rey","year":"2011","unstructured":"Rey, D. Post-exposure prophylaxis for HIV infection. Expert Rev. Anti Infect. Ther. 9, 431\u2013442 https:\/\/doi.org\/10.1586\/eri.11.20 (2011).","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"2511_CR12","doi-asserted-by":"publisher","first-page":"S165","DOI":"10.1093\/CID\/CIV069","volume":"60","author":"C Irvine","year":"2015","unstructured":"Irvine, C. et al. Efficacy of HIV postexposure prophylaxis: systematic review and meta-analysis of nonhuman primate studies. Clin. Infect. Dis. 60, S165\u2013S169 https:\/\/doi.org\/10.1093\/CID\/CIV069 (2015).","journal-title":"Clin. Infect. 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Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512, 74\u201377 https:\/\/doi.org\/10.1038\/nature13594 (2014).","journal-title":"Nature"},{"key":"2511_CR16","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s41586-018-0600-6","volume":"563","author":"EN Borducchi","year":"2018","unstructured":"Borducchi, E. N. et al. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 563, 360\u2013364 https:\/\/doi.org\/10.1038\/s41586-018-0600-6 (2018).","journal-title":"Nature"},{"key":"2511_CR17","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1038\/s41591-018-0130-7","volume":"24","author":"AA Okoye","year":"2018","unstructured":"Okoye, A. A. et al. Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat. Med. 24, 1430\u20131440 https:\/\/doi.org\/10.1038\/s41591-018-0130-7 (2018).","journal-title":"Nat. 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Leveraging antigenic seniority for maternal vaccination to prevent mother-to-child transmission of HIV-1. NPJ Vaccines 7, 87 https:\/\/doi.org\/10.1038\/s41541-022-00505-w (2022).","journal-title":"NPJ Vaccines"},{"key":"2511_CR21","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq1965","volume":"17","author":"V Obregon-Perko","year":"2025","unstructured":"Obregon-Perko, V. et al. Identifying correlates of viral rebound timing and viral control in SHIV-infected infant macaques after ART interruption. Sci. Transl. Med. 17, eadq1965 https:\/\/doi.org\/10.1126\/scitranslmed.adq1965 (2025).","journal-title":"Sci. Transl. Med."},{"key":"2511_CR22","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1016\/J.IMMUNI.2023.04.019","volume":"56","author":"HL Wu","year":"2023","unstructured":"Wu, H. L. et al. Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques. Immunity 56, 1649\u20131663.e5 https:\/\/doi.org\/10.1016\/J.IMMUNI.2023.04.019 (2023).","journal-title":"Immunity"},{"key":"2511_CR23","doi-asserted-by":"publisher","first-page":"S46","DOI":"10.1093\/INFDIS\/JIAA681","volume":"223","author":"C Li","year":"2021","unstructured":"Li, C., Mori, L. & Valente, S. T. The block-and-lock strategy for human immunodeficiency virus cure: lessons learned from didehydro-cortistatin A. J. Infect. Dis. 223, S46\u2013S53 https:\/\/doi.org\/10.1093\/INFDIS\/JIAA681 (2021).","journal-title":"J. Infect. Dis."},{"key":"2511_CR24","doi-asserted-by":"crossref","unstructured":"SenGupta, D. et al. The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy. Sci. Transl. 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