<i>Notch3</i> deletion regulates HIV-1 gene expression and systemic inflammation to ameliorate chronic kidney disease
Anti-retroviral therapy (ART) has decreased human immunodeficiency virus (HIV)-1-associated morbidity. 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 months, 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.
Authors
- Sireesha Yerrathota
- Henrietta Ehirim
- Mackenzie Thornton
- Sumedha Gunewardena (ORCID: https://orcid.org/0000-0003-2097-135X)
- Navneet K. Dhillon (ORCID: https://orcid.org/0000-0001-6582-5757)
- Pravin C. Singhal (ORCID: https://orcid.org/0000-0002-6898-358X)
- Jaya Talreja (ORCID: https://orcid.org/0000-0001-6557-6500)
- Aakriti Chaturvedi
- Anubhav Chakraborty
- Patricio E. Ray (ORCID: https://orcid.org/0000-0003-2223-9584)
- Pamela Vivian Tran (ORCID: https://orcid.org/0000-0003-4619-4376)
- Timothy A. Fields (ORCID: https://orcid.org/0000-0002-6739-6711)
- Mudit Tyagi (ORCID: https://orcid.org/0000-0003-1493-8051)
- Nicole G. Sommer (ORCID: https://orcid.org/0000-0001-6578-0747)
- Madhulika Sharma (ORCID: https://orcid.org/0000-0001-7488-5444)
- Mercedes B. Mcgonigle
- Tao Wang (ORCID: https://orcid.org/0000-0002-7370-7299)
- Johnny Dinh Phan
- Anil Kumar Ram
- Praveen V. Chakravarthi
Institutions
- Albemarle (United States) (US)
- Feinstein Institute for Medical Research (US)
- Thomas Jefferson University (US)
- Wayne State University (US)
- Manchester Academic Health Science Centre (GB)
- University of Virginia Health System (US)
- Detroit Medical Center (US)
- University of Manchester (GB)
- University of Kansas Medical Center (US)
- University of Virginia (US)
Publication Details
- Journal
- Disease Models & Mechanisms
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1242/dmm.052056
- Citations
- 2
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.07
Funders
- National Institute of Mental Health and Neurosciences
- National Institute on Alcohol Abuse and Alcoholism
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases