Notch3 Deletion Regulates HIV-1 Gene Expression and Systemic Inflammation to Ameliorate Chronic Kidney Disease

Overview

Journal bioRxiv

Date 2023 Sep 25

PMID 37745500

Authors

Mackenzie Thornton

Nicole Sommer

Mercedes McGonigle

Anil Kumar Ram

Sireesha Yerrathota

Henrietta Ehirim

Aakriti Chaturvedi

Johnny Dinh Phan

Anubhav Chakraborty

Praveen V Chakravarthi

Sumedha Gunewardena

Mudit Tyagi

Jaya Talreja

Tao Wang

Pravin Singhal

Pamela V Tran

Timothy A Fields

Patricio E Ray

Navneet K Dhillon

Madhulika Sharma

Affiliations

Soon will be listed here.

Abstract

Antiretroviral therapy (ART) has decreased HIV-1 associated morbidity. However, despite ART, immune cells remain latently infected and slowly release viral proteins, 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 several renal cells of the HIV-1 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 diseases (HIV-CKD). We generated HIV-Tg26 mice with Notch3 knocked out (Tg-N3KO). Compared to HIV-Tg26 mice at 3 months, HIV-Tg-N3KO mice showed a marked reduction in renal injury, skin lesions and mortality rate. Bulk RNA sequencing revealed that N3KO not only reduced renal infiltrating cells but significantly reduced the expression of HIV genes. Moreover, Notch3 activated the HIV- promoter and induction of HIV-1 resulted in increased Notch3 activation indicating a feedback mechanism. Further, bone marrow derived macrophages (BMDMs) from HIV-Tg26 mice showed activation of Notch3 indicating systemic effects. Consistent with that, systemic levels of TNF-α, MCP-1 and other inflammatory chemokines and cytokines were reduced in Tg-N3KO mice. Thus, Notch3 inhibition/deletion has a dual therapeutic effect in HIV-CKD and may extend to other HIV-related pathologies.

References

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Shoham N, Cohen L, Yaniv A, Gazit A . The Tat protein of the human immunodeficiency virus type 1 (HIV-1) interacts with the EGF-like repeats of the Notch proteins and the EGF precursor. Virus Res. 2003; 98(1):57-61. DOI: 10.1016/j.virusres.2003.08.016. View

Kilkenny C, Browne W, Cuthill I, Emerson M, Altman D . Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8(6):e1000412. PMC: 2893951. DOI: 10.1371/journal.pbio.1000412. View

Efferson C, Winkelmann C, Ware C, Sullivan T, Giampaoli S, Tammam J . Downregulation of Notch pathway by a gamma-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. Cancer Res. 2010; 70(6):2476-84. DOI: 10.1158/0008-5472.CAN-09-3114. View

Bruggeman L, Thomson M, Nelson P, Kopp J, Rappaport J, Klotman P . Patterns of HIV-1 mRNA expression in transgenic mice are tissue-dependent. Virology. 1994; 202(2):940-8. DOI: 10.1006/viro.1994.1416. View

Putatunda R, Zhang Y, Li F, Yang X, Barbe M, Hu W . Adult neurogenic deficits in HIV-1 Tg26 transgenic mice. J Neuroinflammation. 2018; 15(1):287. PMC: 6182864. DOI: 10.1186/s12974-018-1322-2. View

Waters A, Wu M, Onay T, Scutaru J, Liu J, Lobe C . Ectopic notch activation in developing podocytes causes glomerulosclerosis. J Am Soc Nephrol. 2008; 19(6):1139-57. PMC: 2396929. DOI: 10.1681/ASN.2007050596. View

Arts E, Hazuda D . HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012; 2(4):a007161. PMC: 3312400. DOI: 10.1101/cshperspect.a007161. View

Sakamoto K, Chao W, Katsube K, Yamaguchi A . Distinct roles of EGF repeats for the Notch signaling system. Exp Cell Res. 2004; 302(2):281-91. DOI: 10.1016/j.yexcr.2004.09.016. View

10.

Aqrawi L, Jensen J, Oijordsbakken G, Ruus A, Nygard S, Holden M . Signalling pathways identified in salivary glands from primary Sjögren's syndrome patients reveal enhanced adipose tissue development. Autoimmunity. 2018; 51(3):135-146. DOI: 10.1080/08916934.2018.1446525. View

11.

El Machhour F, Keuylian Z, Kavvadas P, Dussaule J, Chatziantoniou C . Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease. J Am Soc Nephrol. 2014; 26(7):1561-75. PMC: 4483574. DOI: 10.1681/ASN.2013090968. View

12.

Cheng H, Miner J, Lin M, Tansey M, Roth K, Kopan R . Gamma-secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podocyte and proximal tubule formation in developing mouse kidney. Development. 2003; 130(20):5031-42. DOI: 10.1242/dev.00697. View

13.

Li C, Wang H, Kuang W, Ren X, Song S, Zhu H . Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells. J Virol. 2016; 91(1). PMC: 5165213. DOI: 10.1128/JVI.01830-16. View

14.

Mora-Gutierrez J, Rodriguez J, Fernandez-Seara M, Orbe J, Escalada F, Soler M . MMP-10 is Increased in Early Stage Diabetic Kidney Disease and can be Reduced by Renin-Angiotensin System Blockade. Sci Rep. 2020; 10(1):26. PMC: 6949265. DOI: 10.1038/s41598-019-56856-3. View

15.

Dumortier A, Wilson A, MacDonald H, Radtke F . Paradigms of notch signaling in mammals. Int J Hematol. 2005; 82(4):277-84. DOI: 10.1532/IJH97.05099. View

16.

Tang P, Das J, Li J, Yu J, Ray P . An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy. Dis Model Mech. 2020; 13(10). PMC: 7648609. DOI: 10.1242/dmm.045641. View

17.

Klatt N, Chomont N, Douek D, Deeks S . Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol Rev. 2013; 254(1):326-42. PMC: 3694608. DOI: 10.1111/imr.12065. View

18.

Wang X, Chang S, Wang T, Wu R, Huang Z, Sun J . IL7R Is Correlated With Immune Cell Infiltration in the Tumor Microenvironment of Lung Adenocarcinoma. Front Pharmacol. 2022; 13:857289. PMC: 8899515. DOI: 10.3389/fphar.2022.857289. View

19.

Lucas G, Ross M, Stock P, Shlipak M, Wyatt C, Gupta S . Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59(9):e96-138. PMC: 4271038. DOI: 10.1093/cid/ciu617. View

20.

Bruggeman L, Adler S, Klotman P . Nuclear factor-kappa B binding to the HIV-1 LTR in kidney: implications for HIV-associated nephropathy. Kidney Int. 2001; 59(6):2174-81. DOI: 10.1046/j.1523-1755.2001.00732.x. View