Handling Editor: David M. Tobin
ABSTRACT
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. 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, 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. HIV-Tat induced the expression of HIV-1 genes 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. 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: P.T., P.E.R.; Methodology: P.T., J.R.D., J.L., J.Y., P.E.R.; Formal analysis: J.R.D., J.L., J.Y.; Investigation: P.T., J.R.D., J.L.; Writing - original draft: P.T.; Writing - review & editing: J.Y., P.E.R.; Supervision: P.E.R.; Funding acquisition: P.E.R.
Funding
This study was supported by the National Institutes of Health (R01 DK-108368, R01 DK-115968 and R01 DK-04941 to P.E.R.).
Data availability
Tat-HIVAN data is available from GenBank under accession number MT936880.
Supplementary information
Supplementary information available online at https://dmm.biologists.org/lookup/doi/10.1242/dmm.045641.supplemental
- Received May 6, 2020.
- Accepted September 2, 2020.
- © 2020. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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