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

• Published in: Disease models & mechanisms Vol. 13; no. 10
• Main Authors: Tang, Pingtao, Das, Jharna R, Li, Jinliang, Yu, Jing, Ray, Patricio E
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01-10-2020; The Company of Biologists
• Subjects: Acquired immune deficiency syndrome; Adenoviruses; AIDS; AIDS-Associated Nephropathy - genetics; AIDS-Associated Nephropathy - pathology; Albuminuria - complications; Albuminuria - genetics; Amino Acid Sequence; animal model; Animals; Animals, Newborn; Apoptosis; beta-Galactosidase - metabolism; Cell Dedifferentiation; Cell Proliferation; Child; children; Children & youth; Cytokines; Disease Models, Animal; env Gene Products, Human Immunodeficiency Virus - genetics; env Gene Products, Human Immunodeficiency Virus - metabolism; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fibroblasts; Genes; HIV; hiv-1; HIV-1 - genetics; hiv-associated nephropathy; hiv-tat; Human immunodeficiency virus; Humans; Kidney - injuries; Kidney - pathology; Kidneys; Mice, Transgenic; Pathogenesis; Podocytes - metabolism; Podocytes - pathology; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; tat Gene Products, Human Immunodeficiency Virus - chemistry; tat Gene Products, Human Immunodeficiency Virus - metabolism; Teenagers; transgenic mice; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; HIV-1; HIV-associated nephropathy; Animal model; Children; HIV-Tat; Transgenic mice
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.045641

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 (
) 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-
). rAd-
and
control vectors (2×10
) were expressed in the kidney of newborn wild-type and HIV-transgenic (Tg
) FVB/N mice without significant proteinuria (
=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-Tg
mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild-type mice infected with rAd-
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.