Abstract
ABSTRACTModern 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.
Highlights
Modern combined antiretroviral therapies have improved the clinical outcome of children and adolescents living with HIV and decreased the prevalence of HIV-associated nephropathy (HIVAN) in a significant manner
HIV-Transactivator gene (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 recombinant adenoviral vectors (rAd)-Tat vectors, suggesting that HIV-Tat alone does not induce renal disease
Summary
Modern combined antiretroviral therapies (cART) have improved the clinical outcome of children and adolescents living with HIV and decreased the prevalence of HIV-associated nephropathy (HIVAN) in a significant manner. Previous reports in adults [2, 3] and children [4] suggest that HIVAN can occur in people with suppressed viral load. These studies suggest that inflammatory cytokines released by HIVinfected cells can play a role in the pathogenesis of HIVAN independently of the viral load. Taken together, all these findings underscore the importance of acquiring a better understanding of the pathogenesis and treatment of childhood HIVAN during the modern cART era. 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
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