A novel HIV-1 transgenic rat model of childhood HIV-1-associated nephropathy.
BACKGROUND
A characteristic finding of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the presence of heavy proteinuria, focal or global glomerulosclerosis, and microcystic tubular dilatation leading to renal enlargement, and rapid progression to end-stage renal disease (ESRD).


METHODS
We have recently developed the first HIV-1 transgenic rat model that carry a noninfectious HIV-1 DNA construct lacking 3.1 kb of sequence overlapping the gag and pol sequences, and develop many of the clinical lesions seen in HIV-infected patients, including HIVAN. To gain further insight into the pathogenesis of childhood HIVAN, we followed the clinical and renal pathologic outcome of 165 HIV-1 transgenic (HIV-Tg) rats and their respective control littermates for a period of 18 months.


RESULTS
HIV-1 Tg rats progressively developed proteinuria and renal histologic lesions similar to those seen in children with HIVAN, leading to chronic renal failure. By in situ hybridization, HIV-1 genes were detected in glomerular and tubular epithelial cells and infiltrating mononuclear cells, which also expressed the HIV-1 envelop protein gp120. The development of HIVAN was associated with the accumulation of basic fibroblast growth factor (bFGF) in the kidney.


CONCLUSIONS
These data support the notion that HIV-1 plays a direct role in the pathogenesis of HIVAN, by affecting the function and growth of renal epithelial cells, inducing the recruitment of mononuclear cells, and accumulating bFGF in the kidney, even in the absence of viral replication. These rats may provide an excellent model system to study the pathogenesis of childhood HIVAN.
Ray
Patricio E
PE
Children's Research Institute, Center for Genetic Medicine, Children's National Medical Center, Washington, D.C. 20010, USA. Pray@cnmc.org
Liu
Xue-Hui
XH
Robinson
Louis R
LR
Reid
William
W
Xu
Lian
L
Owens
Jennie W
JW
Jones
Odell D
OD
Denaro
Frank
F
Davis
Harry G
HG
Bryant
Joseph L
JL
D016263:AIDS-Associated Nephropathy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure; D002216:Captopril / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015497:HIV-1 / Q000235:genetics; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D012367:RNA, Viral / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; D012367:RNA, Viral; D002216:Captopril