Despite the dramatic improvement in HIV-associated morbidity and mortality from combination antiretroviral therapy, a number of challenges remain including the long- term persistence of viral reservoirs and the persistence of inflammation that results in end organ damage despite therapy, including chronic kidney disease (CKD). Furthermore, it remains unclear as to the major routes of infection of cells intrinsic to the kidney.
Aims 1 and 2 will define the molecules and pathways involved in viral entry, and the steps initiating a robust inflammatory response.
Aim 3 will explore the role of macrophages and dendritic cells in facilitating and sustaining the infection of cells in the kidney.
Aim 4 will explore the inflammatory consequences of persistence of the virus in renal tubule epithelial cells (RTE).
These aims utilize in vitro monocytes-RTE modeling, primary urine derived RTE as well as a humanized mouse model to study both entry and downstream responses. The defined pathways of inflammation will be validated by examination of biopsies from HIV-infected individuals. The information to be gained will impact a major theme in both HIV and chronic kidney disease research, which is understanding the mechanisms that drive chronic inflammation and kidney disease progression and will facilitate the design of better strategies to prevent CKD.

Public Health Relevance

Despite the success of therapy for HIV infection, there is an increased recognition of ongoing organ dysfunction, including the kidney, which remains a challenge. Work proposed in this project uses cell culture systems as well as patient derived specimens to understand how virus entry and persistence in kidney cells contribute to damaging inflammation. Information gained will inform both therapeutic as well as cure strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK056492-17A1
Application #
9204213
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (M6)P)
Project Start
Project End
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
17
Fiscal Year
2017
Total Cost
$256,665
Indirect Cost
$28,047
Name
Baylor College of Medicine
Department
Type
Domestic Higher Education
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Chan, Lili; Asriel, Benjamin; Eaton, Ellen F et al. (2018) Potential kidney toxicity from the antiviral drug tenofovir: new indications, new formulations, and a new prodrug. Curr Opin Nephrol Hypertens 27:102-112
Swanepoel, Charles R; Atta, Mohamed G; D'Agati, Vivette D et al. (2018) Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 93:545-559
Zhong, Fang; Chen, Zhaohong; Zhang, Liwen et al. (2018) Tyro3 is a podocyte protective factor in glomerular disease. JCI Insight 3:
Palau, Laura; Menez, Steven; Rodriguez-Sanchez, Javier et al. (2018) HIV-associated nephropathy: links, risks and management. HIV AIDS (Auckl) 10:73-81
Zhong, Fang; Chen, Haibing; Xie, Yifan et al. (2018) Protein S Protects against Podocyte Injury in Diabetic Nephropathy. J Am Soc Nephrol 29:1397-1410
Hong, Quan; Zhang, Lu; Das, Bhaskar et al. (2018) Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int 93:1330-1343
Fu, Jia; Wei, Chengguo; Zhang, Weijia et al. (2018) Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice. Kidney Int 94:326-345
Corona-Villalobos, Celia P; Shlipak, Michael G; Tin, Adrienne et al. (2017) Predictors of Acute Renal Injury Study (PARIS) among HIV-positive individuals: design and methods. BMC Nephrol 18:289
Gu, Xiangchen; Mallipattu, Sandeep K; Guo, Yiqing et al. (2017) The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis. Kidney Int 92:1178-1193
Wei, Chengguo; Li, Li; Menon, Madhav C et al. (2017) Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis. J Am Soc Nephrol 28:1385-1393

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