Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression.

Bruggeman, Leslie A.; Dikman, Steven; Meng, Charis; Quaggin, Susan E.; Coffman, Thomas M.; Klotman, Paul E.

doi:10.1172/jci119525

Cited by 227 publications

(160 citation statements)

References 42 publications

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“…Studies of these mice, largely by the group of Klotman and their collaborators, have established that expression of HIV genes, presumably modeling the events of renal HIV infection, is sufficient to produce a renal injury in the mouse that is similar to HIVAN in humans. Studies in which kidneys from transgenic mice were transplanted into wild-type controls demonstrated that renal expression of HIV gene products was sufficient to initiate disease (8) and that systemic viral infection or other systemic conditions, such as the immunodeficiency that occurs in humans with HIVAN, were not necessary for the development of nephropathy. The murine models have been further refined to study the effects of selective transgenic insertion of specific HIV genes to determine their relative pathogenicity for the development of HIVAN.…”

Section: Hiv-associated Nephropathymentioning

confidence: 99%

Emerging Paradigms in the Renal Pathology of Viral Diseases

Alpers¹,

Kowalewska²

2007

Clinical Journal of the American Society of Nephrology

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This review considers recent information that illuminates pathogenetic mechanisms that involve three of the major viral infections that cause renal injury in the form of HIV-associated nephropathy, polyoma virus nephropathy, and hepatitis C virus-associated glomerulonephritis.Clin J Am Soc Nephrol 2: S6 -S12, 2007. doi: 10.2215/CJN.00280107 HIV-Associated NephropathyA nephropathy that is associated with HIV infection was identified soon after the epidemic of HIV/AIDS first became recognized in the early 1980s. HIV-associated nephropathy (HIVAN) is a combined glomerular and tubular injury that is characterized by a collapsing glomerulopathy (CG) with collapse of glomerular capillary structures and a striking hyperplasia of podocytes, microcystic transformation of renal tubules, and concomitant and likely nonspecific interstitial inflammation and fibrosis consequent to the glomerular and tubular injuries (Figure 1). From a pathology standpoint, three major areas of investigation have led to a deeper understanding of this lesion.The first of these addresses the issue of whether HIVAN is a direct consequence of viral infection of the renal parenchyma or is a secondary consequence of systemic infection. Cohen et al.(1) first reported the presence of HIV RNA in podocytes as revealed by in situ hybridization (ISH) in 1989, a finding that was supported by microdissection studies of Kimmel et al. (2). These studies were difficult to validate because of the failure of others to replicate these findings using conventional techniques of ISH, the inability to demonstrate the presence of viral peptides in renal parenchymal cells by immunohistochemistry, and the inability to demonstrate appropriate receptors for viral entry into cells, namely CD4 and the chemokine receptors CXCR4 or CCR5, on renal parenchymal cells (3). This created a conundrum in that a mechanism for viral entry into renal cells could not be defined. Some but not all of the difficulties were resolved by a more sophisticated form of ISH, which is based on a technique that detects forms of viral DNA that are characteristic of replicating virus (4 -6). With these techniques, it was possible to substantiate the findings of Cohen et al. and convincingly demonstrate HIV infection of podocytes and tubular epithelial cells.A second key development concomitant with the demonstration of HIV infection of human renal epithelial cells was the development of murine models of HIVAN. The best studied of these involves the Tg26 mouse: Mice are made transgenic for a nearly whole-length HIV virus but with a deletion of HIV gag and pol genes to render the virus nonreplicative (7). Studies of these mice, largely by the group of Klotman and their collaborators, have established that expression of HIV genes, presumably modeling the events of renal HIV infection, is sufficient to produce a renal injury in the mouse that is similar to HIVAN in humans. Studies in which kidneys from transgenic mice were transplanted into wild-type controls demonstrated that renal expression of HIV gene...

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Section: Hiv-associated Nephropathymentioning

confidence: 99%

Emerging Paradigms in the Renal Pathology of Viral Diseases

Alpers¹,

Kowalewska²

2007

Clinical Journal of the American Society of Nephrology

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“…The homozygous transgenic mice develop cachexia and die by 2 months, a phenotype reminiscent of the AIDS-associated wasting syndrome (7,24,29,31). Development of HIVAN in this model depends on the presence of the HIV-1 genome in the kidney because wild-type kidneys transplanted into the HIV-1 trangenic background remain free of disease whereas transgenic kidneys transplanted into a wild-type background develop HIVAN (32).…”

mentioning

confidence: 99%

Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3

Gharavi

Ahmad

Wong

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection with distinct pathologic features. Introduction of the HIV-1 genome into mice results in a renal disease with all of the histologic and clinical hallmarks of HIVAN on the FVB͞N genetic background (TgFVB). We assessed the influence of genetic background on the development or progression of HIVAN by making F1 hybrids of TgFVB with five other inbred strains (CBA, DBA͞2, CAST͞Ei, C3H͞He, BALB͞c) and determining phenotypes relevant to renal failure among transgenic offspring (histology, blood urea nitrogen, proteinuria, serum albumin, and serum cholesterol). We found striking variation in phenotypes among F1s, ranging from severe renal disease to no renal disease whatsoever (P < 0.001 for ANOVA across all groups). To map genes responsible for this variation, we produced a backcross of TgFVB͞CAST F1 ؋ TgFVB. By genome-wide analysis of linkage in 185 heterozygous transgenic backcross mice, we identified a locus on chromosome 3A1-3, HIVAN1, that showed highly significant linkage to renal disease [logarithm of odds (lod) score 4.9 at D3Mit203, accounting for 15% of the variance in renal disease]. Other loci on chromosomes 11, 14, and 16 were suggestive of linkage to renal disease, and a locus on chromosome 9 influenced serum cholesterol but not nephropathy. Interestingly, HIVAN1 is syntenic to human chromosome 3q25-27, an interval showing suggestive evidence of linkage to various nephropathies. These findings demonstrate a strong genetic influence on HIVAN and demonstrate a major renal disease susceptibility locus on mouse chromosome 3A1-3.

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“…They carried out transplantation of kidneys between normal and HIV-transgenic mice. [1] These investigators showed that HIV-transgene-containing mice developed renal lesions that mimic HIVAN. This study suggested that the presence of HIV-1 gene products is necessary and sufficient in the development of renal lesions.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5] The latter is characterized by focal glomerulosclerosis and tubulointerstitial lesions. [6] Acute renal failure has frequently been reported as a result of tubular cell injury (apoptosis and necrosis) in HIV-1-infected patients.…”

Section: Introductionmentioning

confidence: 99%