JAC Advance Access published online on March 13, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg175
© 2003 by The British Society for Antimicrobial Chemotherapy
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original article
1 Division of Nephrology,
Box 1243, Mount Sinai School of Medicine, One Gustave L. Levy Place,
New York,
NY 10029
* Corresponding author. E-mail: peter.nelson{at}mssm.edu.
Received 2 October 2002
; revised 20 December 2002
; accepted 25 January 2003
Cumulative evidence suggests that human immunodeficiency
virus-associated nephropathy (HIVAN), the third leading cause of
end-stage renal disease in African-Americans, may respond to therapeutic
strategies that interrupt HIV-1 expression in infected renal epithelium.
We recently demonstrated that suppression of HIV-1 transcription
in infected glomerular visceral epithelial cells by flavopiridol,
a small-molecule inhibitor of the cyclin-dependent kinases required
for HIV-1 promoter activity, reversed HIV-induced proliferation
and dedifferentiation in vitro. To address whether
flavopiridol could ameliorate HIV-induced renal disease, we utilized
a well-established HIV-1 NL4-3 transgenic mouse model of HIVAN.
HIV-1 proviral transgene expression in whole kidney was markedly
suppressed by a 20 day treatment with flavopiridol. Following treatment,
histopathological, serological and urinary indices of nephrosis
were normalized in flavopiridol-treated but not in vehicle-treated
transgenics. Microarray analysis showed that 82% of the
dysregulated genes in HIVAN kidney were normalized to control levels
by flavopiridol, whereas continued dysregulation of most of the
remaining 18% was attributable to an effect from flavopiridol
alone. These results demonstrate for the first time that targeting
the cyclin-dependent kinases that support HIV-1 expression can ameliorate
HIV-induced disease in an animal model.
Keywords: kidney, renal, therapy, AIDS, model
Amelioration of nephropathy in mice expressing
HIV-1 genes by the cyclin-dependent kinase inhibitor flavopiridol
2 Department of
Pathology, Columbia University College of Physicians & Surgeons,
New York,
NY 10032
3 Aventis Pharmaceuticals,
Inc., Bridgewater, NJ 08807
4 Division
of Infectious Diseases,
Mount Sinai School of Medicine, New York, NY 10029, USA
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. A. Bruggeman Viral Subversion Mechanisms in Chronic Kidney Disease Pathogenesis Clin. J. Am. Soc. Nephrol., July 1, 2007; 2(Supplement_1): S13 - S19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Albaqumi, T. J. Soos, L. Barisoni, and P. J. Nelson Collapsing Glomerulopathy J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2854 - 2863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Martinka and L. A. Bruggeman Persistent NF-{kappa}B activation in renal epithelial cells in a mouse model of HIV-associated nephropathy Am J Physiol Renal Physiol, March 1, 2006; 290(3): F657 - F665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Diwan, J. J. Lacasse, and L. M. Schang Roscovitine Inhibits Activation of Promoters in Herpes Simplex Virus Type 1 Genomes Independently of Promoter-Specific Factors J. Virol., September 1, 2004; 78(17): 9352 - 9365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gherardi, V. D'Agati, T.-H. T. Chu, A. Barnett, A. Gianella-Borradori, I. H. Gelman, and P. J. Nelson Reversal of Collapsing Glomerulopathy in Mice with the Cyclin-Dependent Kinase Inhibitor CYC202 J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1212 - 1222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hiromura and S. J. Shankland Negatively Regulating the Cell Cycle Can Be Positive J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1361 - 1362. [Full Text] [PDF]
|
|