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An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

Pingtao Tang, Jharna R. Das, Jinliang Li, Jing Yu, View ORCID ProfilePatricio E. Ray
doi: https://doi.org/10.1101/2020.05.06.081851
Pingtao Tang
1Center for Genetic Medicine Research, Children’s National Hospital, University of Virginia School of Medicine, Charlottesville, VA
2The George Washington University School of Medicine, Washington DC
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Jharna R. Das
1Center for Genetic Medicine Research, Children’s National Hospital, University of Virginia School of Medicine, Charlottesville, VA
2The George Washington University School of Medicine, Washington DC
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Jinliang Li
1Center for Genetic Medicine Research, Children’s National Hospital, University of Virginia School of Medicine, Charlottesville, VA
2The George Washington University School of Medicine, Washington DC
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Jing Yu
3Child Health Research Center, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA
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Patricio E. Ray
3Child Health Research Center, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA
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  • ORCID record for Patricio E. Ray
  • For correspondence: Pray@virginia.edu
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Abstract

Background Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments.

Objectives To define whether the HIV-1 trans-activator (Tat) gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN.

Design/Methods An HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vectors (rAd-Tat). rAd-Tat and LacZ control vectors (2 × 109) were expressed in the kidney of newborn wild type and HIV-transgenic (Tg26) FVB/N mice without significant proteinuria (n = 5 - 8 per group). Mice were sacrificed 7 and 35 days later to assess their renal outcome, the expression of HIV-genes and growth factors, and markers of cell growth and differentiation by RT-qPCR, immunohistochemistry, and/or Western blots.

Results HIV-Tat induced the expression of HIV-1 genes (env) and heparin binding growth factors in the kidney of HIV-Tg26 mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild type mice infected with rAd-Tat vectors, suggesting that HIV-Tat alone does not induce renal disease.

Conclusion This new mouse model of childhood HIVAN highlights the critical role that HIV-Tat plays in the pathogenesis of HIVAN, and could be used to study the pathogenesis and treatment of HIVAN in children and adolescents.

Summary statement We developed a new inducible mouse model system of childhood HIV-associated nephropathy, and demonstrated that HIV-Tat plays a critical role in this renal disease acting in synergy with other HIV-1 genes and heparin binding cytokines.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 08, 2020.
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An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy
Pingtao Tang, Jharna R. Das, Jinliang Li, Jing Yu, Patricio E. Ray
bioRxiv 2020.05.06.081851; doi: https://doi.org/10.1101/2020.05.06.081851
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An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy
Pingtao Tang, Jharna R. Das, Jinliang Li, Jing Yu, Patricio E. Ray
bioRxiv 2020.05.06.081851; doi: https://doi.org/10.1101/2020.05.06.081851

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