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Current treatment approaches that aim to reactivate latent virus and eliminate infected cells, termed \u201cshock and kill,\u201d hold promise but have yet to demonstrate meaningful reservoir reduction in vivo. In this study, we explored combining ciapavir, a Smac mimetic latency-reversing agent, with adeno-associated virus\u2013delivered (AAV-delivered) eCD4-Ig to treat antiretroviral therapy\u2013suppressed, SHIV-infected rhesus macaques. We could demonstrate that a Smac mimetic can induce modest reactivation of the latent SHIV reservoir, as evidenced by transient increases in plasma viremia. However, while AAV-expressed eCD4-Ig conferred partial protection against intrarectal SHIV challenge in uninfected animals, neither eCD4-Ig nor ciapavir reduced the viral reservoir in SHIV-infected rhesus macaques, as determined by total SHIV DNA and a 5-target intact provirus detection assay. Animals treated with the combination showed no significant differences in viral rebound kinetics post\u2013analytical treatment interruption compared with controls. Additionally, repeated ciapavir dosing resulted in adverse effects in some animals, suggesting potential toxicity with repeat administration. These findings highlight the challenges in reducing viral reservoirs using this shock-and-kill approach, particularly in SHIV-infected models, and suggest that further optimization of both latency-reversing agent and immune-mediated clearance strategies is required.<\/jats:p>","DOI":"10.1172\/jci187961","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T18:00:52Z","timestamp":1773597652000},"source":"Crossref","is-referenced-by-count":0,"title":["Smac mimetic combined with eCD4-Ig reverses latency without reducing SHIV reservoirs in rhesus macaques"],"prefix":"10.1172","volume":"136","author":[{"given":"Lars","family":"Pache","sequence":"first","affiliation":[{"name":"Center for Therapeutics Discovery, NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John K.","family":"Bui","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."},{"name":"Department of Medicine and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9644-361X","authenticated-orcid":true,"given":"Lindsay M.","family":"Klouser","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8736-8523","authenticated-orcid":true,"given":"Christine M.","family":"Fennessey","sequence":"additional","affiliation":[{"name":"AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander C.","family":"Noyola","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Einhaus","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Stensland","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isai","family":"Leguizamo","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abubakarr A.","family":"Koroma","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Teriete","sequence":"additional","affiliation":[{"name":"Center for Therapeutics Discovery, NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1258-7369","authenticated-orcid":true,"given":"W.L. 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