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However, despite ART, immune cells remain latently infected, leading to chronic inflammation and HIV-1-associated comorbidities. New strategies are needed to target viral proteins and inflammation. We found activation of Notch3 in renal cells of the HIV-1 transgenic mouse model (HIV-Tg26) and in patients with HIV-associated nephropathy. We hypothesized that targeting NOTCH3 activation constitutes an effective therapy for HIV-related chronic kidney disease. We generated HIV-Tg26 mice with Notch3 knocked out (Tg-N3KO). Compared to HIV-Tg26 mice at 3\u2005months, Tg-N3KO mice showed a marked reduction in renal injury, skin lesions and mortality rate. They also showed reduced renal infiltrating cells and significantly reduced expression of HIV genes. Moreover, Notch3 activated the HIV long terminal repeat promoter, and induction of HIV-1 increased Notch3 activation, indicating a feedback mechanism. Further, bone marrow-derived macrophages from HIV-Tg26 mice showed activation of Notch3, indicating systemic effects. Consistent with that observation, systemic levels of TNF and MCP-1 were reduced in Tg-N3KO compared to HIV-Tg26 mice. Thus, Notch3 deletion\/inhibition has a dual-therapeutic effect in HIV-related chronic kidney disease, which might extend to other HIV-related pathologies.<\/jats:p>","DOI":"10.1242\/dmm.052056","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T02:19:56Z","timestamp":1738808396000},"source":"Crossref","is-referenced-by-count":4,"title":["<i>Notch3<\/i>\n                    deletion regulates HIV-1 gene expression and systemic inflammation to ameliorate chronic kidney disease"],"prefix":"10.1242","volume":"18","author":[{"given":"Mackenzie","family":"Thornton","sequence":"first","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Sommer","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"McGonigle","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Kumar Ram","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sireesha","family":"Yerrathota","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrietta","family":"Ehirim","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakriti","family":"Chaturvedi","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Dinh Phan","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anubhav","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. Praveen","family":"Chakravarthi","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 2 Department of Pathology and Laboratory Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumedha","family":"Gunewardena","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 3 Department of Cell Biology and Physiology , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mudit","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University 4 Department of Medicine , , Philadelphia, PA 19107 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaya","family":"Talreja","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine and Detroit Medical Center 5 Division of Pulmonary, Critical Care and Sleep Medicine , , Detroit, MI 48201 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"The University of Manchester 6 Department of Biology, Medicine and Health , , Manchester M13 9PT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pravin","family":"Singhal","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, Feinstein Institute for Medical Research, Zucker School of Medicine at Hofstra-Northwell 7 , New York, NY 11021 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela V.","family":"Tran","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 3 Department of Cell Biology and Physiology , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Fields","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 2 Department of Pathology and Laboratory Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio E.","family":"Ray","sequence":"additional","affiliation":[{"name":"University of Virginia School of Medicine 8 Child Health Research Center and Department of Pediatrics , , Charlottesville, VA 22903 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navneet K.","family":"Dhillon","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7488-5444","authenticated-orcid":false,"given":"Madhulika","family":"Sharma","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 1 Department of Internal Medicine , , Kansas City, KS 66160 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"2025040306213902000_DMM052056C1","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1080\/08916934.2018.1446525","article-title":"Signalling pathways identified in salivary glands from primary Sj\u00f6gren's syndrome patients reveal enhanced adipose tissue development","volume":"51","author":"Aqrawi","year":"2018","journal-title":"Autoimmunity"},{"key":"2025040306213902000_DMM052056C2","doi-asserted-by":"publisher","first-page":"a007161","DOI":"10.1101\/cshperspect.a007161","article-title":"HIV-1 antiretroviral drug therapy","volume":"2","author":"Arts","year":"2012","journal-title":"Cold Spring Harb. 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