Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy

Zhong, Jian; Zuo, Yiqin; Ma, Ji; Fogo, Agnes B.; Jolicoeur, Paul; Ichikawa, Iekuni; Matsusaka, Taiji

doi:10.1111/j.1523-1755.2005.00497.x

Cited by 118 publications

(103 citation statements)

References 56 publications

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“…For example, the absence of overt nephropathy in mice with podocyte-specific expression of the nef gene may be attributable to the genetic background (C57BL/6J) used (57). Consistent with these data, mice that expressed a HIV-1 transgenes in glomerular podocytes developed HIVAN only in the FVB/N but not the C57BL/6J genetic background (80). These genetic modifiers may be identified by intercrossing that is susceptible to resistant strains.…”

Section: Genetic Susceptibility and Hivansupporting

confidence: 70%

Genetic Susceptibility, HIV Infection, and the Kidney

Kiryluk

Martino

Gharavi

2007

Clinical Journal of the American Society of Nephrology

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In recent years, the sequencing of mammalian and microbial genomes has provided the opportunity to study how genetic variation in the host and pathogen influence the course of infectious disease. In the case of HIV-1 infection, such studies have led to identification of key viral proteins that determine pathogenicity, immune evasion, or drug resistance. In addition, candidate gene association studies have uncovered a large number of host genetic variants that influence the outcome of infection and some organ-specific complications. HIV-associated nephropathy (HIVAN) is a pathologically distinct complication of HIV infection. Interindividual variability in incidence, skewed ethnic distribution, and familial aggregation of HIVAN with other forms of ESRD have suggested genetic susceptibility as a major contributing factor. This article reviews the host genetic factors that influence the course of HIV-1 infection and discusses murine models that have increased the understanding of HIVAN pathogenesis and demonstrated the role of genetic background on determination of disease.

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Section: Genetic Susceptibility and Hivansupporting

confidence: 70%

Genetic Susceptibility, HIV Infection, and the Kidney

Kiryluk

Martino

Gharavi

2007

Clinical Journal of the American Society of Nephrology

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“…This has clear pathophysiologic consequences because the contribution from dying epithelial cells to the loss of organ function becomes greatly amplified by the additional loss of cellular function from proliferating and dedifferentiated epithelium that surrounds the initial sites of injury. Although this speculative "best fit" model has not been investigated directly in CG, preliminary studies to characterize the earliest stages of development of CG in some murine models have found that apoptosis or necrosis of renal epithelium occurs before the aberrant proliferation of renal epithelium becomes apparent (80,84,85,94,118).…”

Section: Models Of Pathogenesismentioning

confidence: 99%

Collapsing Glomerulopathy

Albaqumi¹,

Soos²,

Barisoni³

et al. 2006

Journal of the American Society of Nephrology

150

183

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Collapsing glomerulopathy (CG) has become an important cause of ESRD. First delineated from other proteinuric glomerular lesions in the 1980s, CG is now recognized as a common, distinct pattern of proliferative parenchymal injury that portends a rapid loss of renal function and poor responses to empiric therapy. Notwithstanding, the rise in disorders that are associated with CG, the identification of the first susceptibility genes for CG, the remarkable increase in murine modeling of CG, and promising preclinical testing of new therapeutic strategies suggest that the outlook for CG as a poorly understood and therapeutically resistant renal disease is set to change in the future. This focused review highlights recent advances in research into the pathogenesis and treatment of CG.

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“…These studies have indicated that the product of the HIV gene nef, a gene that is involved in viral replication, is a particularly important contributor to the development of nephropathy, although it is not alone sufficient to produce this injury (9 -11). Murine models in which transgenic expression of HIV is limited to podocytes (resulting from the use of a nephrin promoter construct) have been created recently and show that HIV infection of podocytes is sufficient to produce the CG phenotype of HIVAN (12).…”

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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Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy

Abstract: The present study demonstrates that podocyte-restricted expression of HIV-1 gene products is sufficient for the development of collapsing glomerulosclerosis in the setting of susceptible genetic background.

Cited by 118 publications

References 56 publications

Genetic Susceptibility, HIV Infection, and the Kidney

Genetic Susceptibility, HIV Infection, and the Kidney

Collapsing Glomerulopathy

Emerging Paradigms in the Renal Pathology of Viral Diseases

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