UP FRONT MATTERSBrief Reviews

Transgenic and Infectious Animal Models of HIV-Associated Nephropathy

Paul Rosenstiel, Ali Gharavi, Vivette D'Agati and Paul Klotman
JASN November 2009, 20 (11) 2296-2304; DOI: https://doi.org/10.1681/ASN.2008121230

Abstract

HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Transgenic and infectious models of HIVAN faithfully recapitulate the human disease and are important tools in advancing our understanding of disease pathogenesis, genetic susceptibility, and therapeutic intervention beyond the inhibition of viral replication. This review discusses the available transgenic murine models and infectious models of HIVAN in mice, rats, nonhuman primates, and felines. Particular emphasis is given to cell type–specific HIV expression as well as partial HIV genome expression used to map HIV-1 Nef and Vpr as pathologic determinants.

HIV-associated nephropathy (HIVAN) was first reported in 1984, when a small group of Haitian and African American patients with HIV presented with kidney disease without other risk factors.1 During the subsequent 24 years, HIVAN became the leading cause of ESRD in HIV-1– seropositive individuals and the third leading cause of ESRD in patients of African descent, the population comprising the vast majority of HIVAN cases. HIVAN prevalence in HIV-infected patients of African descent is estimated to be between 3 and 12%, putting global projections as high as 3 million prevalent cases.2,3 The results of a large number of studies that addressed HIVAN pathogenesis have led to a better understanding of the disease and improvements in clinical practice. Expert guidelines have now changed to recommend highly active antiretroviral therapy for patients with renal disease.4,5 Much of our knowledge of disease pathogenesis has derived from transgenic mouse models that express all or parts of the HIV genome. These animal models have been able to recapitulate many aspects of human HIVAN.

Clinically, HIVAN is characterized by proteinuria, often nephrotic range, and decreased renal function.6,7 Peripheral edema and hypertension are seen less often in HIVAN compared with other forms of renal disease, suggesting salt wasting perhaps as a result of tubulointerstitial disease.8 Renal ultrasound shows large echogenic kidneys, and urinalysis usually shows only elevated protein excretion and occasional hyaline casts.9,10 Although this kind of clinical data and diagnostic workup suggests the presence of HIVAN, the diagnosis can be made only by biopsy.

In HIVAN, the kidneys are often grossly enlarged, and biopsies demonstrate a number of distinct histopathologic changes. Glomerular disease is classically characterized by the presence of collapsing FSGS with retraction of the glomerular basement membrane.11 Focal microcystic dilation (three times the normal diameter of the renal tubules) is also present and accompanied by epithelial flattening of the cyst-lining cells.12 In addition, interstitial infiltration of lymphocytes and macrophages as well as interstitial fibrosis are often present.13 Ultrastructural changes include podocyte dedifferentiation and loss of foot process architecture as well as aberrant proliferation.14 Parietal epithelial cell proliferation, atrophy, apoptosis, and loss of polarization have also been reported.14 Immunohistochemical analysis reveals a loss of differentiation markers in podocytes (WT-1 synaptopodin, GLEPP-1, and podocalyxin) and an increase in the proliferation marker Ki-67.14–17 Renal tubular epithelial cells show similar loss of differentiation and inappropriate localization of the Na-K-ATPase to the apical and lateral membrane.18

This review describes the available murine and nonhuman primate models of HIVAN that have been useful in advancing our knowledge of the pathogenesis of HIVAN. A summary of the HIVAN animal models discussed is shown in Table 1.

View this table:
Table 1.

Summary of 32 transgenic murine HIVAN models that are discussed in this reviewa

Transgenic Mouse Models

Tg26 HIVAN Mouse Model

In 1991, the first HIVAN transgenic mouse model, termed “transgenic 26”(Tg26), was created using a replication-deficient version of HIV as the integrated transgene (see Dickie et al.19 in Table 1). Specifically, a 3.1-kb deletion was made in the pNL4-3 HIV proviral genomic construct spanning HIV-1 gag and pol from bp 1443 to 4551. Three separate transgenic founding lines that developed renal disease were generated: Tg22c, Tg25, and Tg26. The first two developed renal disease so severe that the progeny were unable to survive to breeding age, whereas the Tg26 heterozygotes survived long enough to generate offspring. Thus, the Tg26 line was sustained through heterozygous breeders.

The mRNA expression of HIV in the Tg26 model is readily detected in skin, skeletal muscle, and kidneys of transgenic mice despite the intrinsic limitations of HIV-1 tat activity in rodent cells. Expression is also weakly detected in brain, eye, gastrointestinal tract, spleen, and thymus. Although transgene expression is one determinant of host cellular responses, it is the relative abundance of spliced or unspliced HIV mRNA that determines which gene products will be made in a particular cell type. In a natural infection, the HIV protein Rev is an early gene product generated from multiply spliced mRNA. As Rev accumulates, it protects and facilitates unspliced HIV mRNA transport to the cytoplasm. The unspliced mRNA then serves as the template for the subsequent HIV gene products. In the Tg26 model, unspliced message was readily detected in lymphoid tissue (thymus and spleen) and kidney while multiply spliced messages predominated in the other tissues.20 This result suggests that Rev functionality is conserved in certain organs including hematopoietic tissues and the kidney in the murine transgenic model.

The renal manifestations of these transgenic lines are severe and bear a striking resemblance to human HIVAN (Figure 1). Homozygous Tg26 mice are runted and die before day 40, whereas heterozygous mice seem normal at birth but develop heavy proteinuria, elevated blood urea nitrogen, edema, ascites, and hypoalbuminemia between 60 and 250 d. Death from uremia typically occurs 2 wk after the onset of edema. Histologically, Tg26 kidneys develop diffuse segmental and global glomerulosclerosis of the collapsing variant, microcystic tubular changes, and monocytic interstitial infiltrate. Ultrastructurally, the podocytes show foot process effacement also characteristic of the human disease. At the time the mice were first generated, it was unclear whether renal expression of HIV genes was responsible for the HIVAN phenotype; however, renal transgene levels correlate with disease severity between different transgenic lines and also temporally with disease progression in the Tg26 line. Heterozygous Tg26 mice do not develop CD4+ T cell depletion, so it was thought to be unlikely that the renal disease observed was a result of immune dysregulation.21 Follow-up studies using reciprocal renal transplantation confirmed the hypothesis that renal expression of the HIV genome was responsible for disease phenotype.22 Nontransgenic mice receiving a Tg26 kidney developed HIVAN-like disease, whereas Tg26 mice receiving a nontransgenic kidney remained healthy. This result demonstrates that HIV gene expression in the kidney is both necessary and sufficient in the FVB background to cause disease in the mouse model.

Figure 1.
Figure 1.

Renal disease in the HIV transgenic mouse resembles human HIVAN. (a and b) Periodic acid-Schiff stains showing collapsing glomeruli with podocyte proliferation in the HIVAN mouse model (Tg26-FVB/N 3A1–3 CAST) and human disease, respectively. PAS (c) or silver (d) stain showing renal tubular microcystic change in the HIVAN mouse model and human disease, respectively. Magnifications: ×600 in a and b; ×200 in c and d.

This hypothesis was corroborated in human HIVAN biopsies, in which HIV mRNA and proviral DNA were found in both podocytes and tubular epithelial cells.23 The murine model of the microcystic epithelium also provides a unique insight to its pathogenesis. These flattened epithelial cells no longer express the HIV transgene despite its ubiquitous presence in all murine cells.18 This suggests that microcysts may result when the differentiated tubular epithelium transforms or is replaced by a primitive cell type, perhaps with little transcriptional capacity to support HIV gene expression.

Because the Tg26 mouse line faithfully reproduces characteristic HIVAN, it has been a valuable tool to probe the pathogenesis of disease. In vitro data demonstrating that HIV induces cell hypertrophy and cell-cycle dysregulation that is mediated by the viral protein Vpr were confirmed in vivo using the Tg26 model.24 Fas-FasL–mediated apoptosis in tubular epithelial cell lines was also subsequently characterized in the Tg26 model.25,26 The upregulation of several novel host factors, including FAT10 and Podocan, has been confirmed by immunohistochemistry in the Tg26 mouse model.27,28 The reproducibility of results in the murine model has spurred investigation of HIVAN cell biology in murine cell lines. Advantages of this approach include the generation of knockout cell lines or easily maintained cell lines of specific cell types such as podocytes by conditional immortalization.29

The Tg26 mouse has also been a tool to investigate the genetic predilection for HIVAN. The initial Tg26 mouse line was generated on the FVB/N inbred mouse strain. Whereas this strain is susceptible to disease, Tg26 mice bred onto the mixed FVB/CAST background mouse strain and others do not develop disease. Using genome-wide linkage analysis, the genetic loci and genes responsible for disease penetrance can be determined providing candidates and pathways to examine in the human disease. Notably, mouse chromosome 3A1 to 3, a region syntenic to human chromosome 3q25 to 27, has been identified as a HIVAN-susceptibility locus (see Gharavi et al. 2003 in Table 1)30,31; however, when the FVB/N allele in this locus is selectively replaced with the CAST allele, the HIV transgenic mice show accelerated disease progression. Taken together, these studies suggest that HIVAN is a multifactorial disease and that variation in susceptibility likely results from the combined effect of protective and permissive nephropathy alleles (see Chan 200831 in Table 1). In addition, the nondiabetic ESRD African American major effect risk gene MYH9 that was identified in two large independent genetic screens was subsequently identified in murine genetic studies as well.32,33

Tissue- and Cell Type–Specific HIV Expression

HIV transgenic mouse models can determine how different cell types and renal compartments contribute to the overall disease process. In natural infection, HIV infects podocytes, tubular epithelial cells throughout the nephron, and infiltrating lymphocytes and macrophages. In the Tg26 model, HIV expression is ubiquitous; therefore, tissue-specific expression models have been designed to study each compartment individually.

Transgenic mice expressing the full HIV genome expressed under a CD4 promoter were designed to restrict expression to immune cells (see Hanna et al.34 in Table 1); however, CD4 expression is promiscuous, and HIV was also produced in other kidney compartments, including glomerular cells. Nonetheless, this model shows characteristics of HIVAN. Specifically, transgenic mice with HIV under the control of the CD4 promoter develop severe tubular atrophy, tubulointerstitial nephritis, and fibrosis. FSGS was not originally reported in the CD4/HIV mice, although transgene expression was abundant in the glomerulus. In subsequent studies, however, using the same transgenic line, FSGS was observed.35,36 Extensive tubular dilation is also seen, although the kidneys are grossly smaller than those of control littermates. This is in contrast to the Tg26 model and human HIVAN, in which the kidneys are enlarged up to 25%. The cause for this difference is unclear. Further studies showed that HIV-1 Nef was the major determinant of this phenotype when compared with the other HIV genes under the control of the CD4 promoter (see Hanna et al.37 in Table 1). The Nef PxxPxxP (amino acids 72 through 78) motif (an SH3-binding domain), the myristoylation site G2, and sequences amino acids 25 through 35 and amino acids 57 through 66 all are required for disease pathogenesis in the CD4 model (see Hanna et al.35,36 in Table 1). Subsequent studies suggested that Nef mediates podocyte proliferation and dedifferentiation through its interaction with Src kinase and activation of the Stat3 and mitogen-activated protein kinases 1 and 2 pathways.38–40

Podocyte-specific expression of a HIVΔgag/pol/env construct in transgenic mice shows extensive HIVAN pathology. In these mice, the HIV LTR promoter was replaced by the podocyte-specific nephrin promoter Nphs1 (see Zhong et al.41 in Table 1). These mice exhibit proteinuria at 3 wk and have increased mortality compared with wild-type littermates. Collapsing FSGS with mesangial expansion is seen, and podocytes show diminished foot processes, an immature cuboid shape, and lack of the marker genes WT-1 and synaptopodin typical of differentiated podocytes. In addition to the glomerular phenotype, these mice also develop interstitial fibrosis, tubular microcystic dilation, and tubule cell proliferation as determined by Ki-67 staining. Glomerular cell proliferation is also observed, but it is unclear whether the cells invading Bowman's space are podocytes or parietal cells that may even be podocyte precursors.42

Both the podocyte-specific and CD4-driven HIV transgenic models show tubular microcystic dilation despite the lack of transgene expression in the renal tubule itself. In addition, the renal tubule phenotype can occur independent of both an HIV-expressing lymphocytic infiltrate (not seen in this podocyte model) and FSGS (not seen in early reports of the CD4/HIV model34). A possible explanation is that podocyte expression generates HIV viral proteins in the glomerulus that are released into the circulation or into the urinary space with subsequent exposure to the tubules, but this remains unproved.

Single HIV Gene and Gene Deletion HIVAN Models

Several transgenic models, including the aforementioned CD4/HIVnef only model, have attempted to determine the role of specific HIV genes in the pathogenesis of HIVAN. The results have been consistent, implicating both HIV-1 Nef and Vpr as the major contributors. Expression of an HIVΔgag/pol/nef transgene in mice causes FSGS and microcystic tubular dilation but not podocyte proliferation (see Kajiyama et al.43 in Table 1); however, the FSGS is exacerbated when this mouse line is backcrossed to a Nef-only transgenic line (see Dickie et al. 44 in Table 1), implicating a role for both Nef and another HIV gene in HIVAN pathogenesis. A separate study examined a modified Tg26 model whereby vpr, nef, or both were additionally deleted (see Dickie et al.45 in Table 1). In this study, only mice carrying an intact Vpr gene developed proteinuria, and FSGS with tubular dilation was observed even in the Nef-deleted model. Furthermore, a Vpr-tat–only transgenic model developed a HIVAN-like phenotype that included both glomerular and tubular diseases, particularly in nursing female mice.45 Crosses between the Vpr-tat mouse and the Vpr-deleted mouse restored HIVAN pathology in its entirety. Interestingly, when Vpr was preferentially expressed in monocytes/macrophages using the c-fms promoter, renal disease was confined to the glomerular compartment.45 Possible explanations include expression of Vpr in glomerular macrophages, “off-target” expression of Vpr in glomerular mesangial cells, and an effect of circulating Vpr on the downstream glomerulus. Nonetheless, because Vpr is capable of causing glomerular pathology either alone or in conjunction with tubular pathology depending on the model system, Vpr is likely a direct contributor to disease in both compartments. Vpr-expressing constructs in mice, however, have not shown the podocyte proliferation that is observed in human HIVAN.

Nef and Vpr have also been independently expressed in podocytes specifically using the nephrin promoter (see Zuo et al.46 in Table 1). Podocyte-specific expression of either Nef or Vpr alone causes proteinuria by 10 wk and glomerulosclerosis and tubular injury between 4 and 6 mo in transgenic mice. When these mouse lines were crossed with each other to create a podocyte-specific Vpr/Nef transgenic line, the effect on disease was synergistic. Severe glomerulosclerosis and tubulointerstitial injury was seen in all Vpr/Nef mice by just 3 wk of age. Podocyte-specific expression of the single HIV genes Vif, Tat, Vpu, and Rev resulted in no renal injury.46

A doxycycline-inducible podocyte-specific Vpr transgenic model that used the podocin promoter also showed HIVAN pathology 16 wk after induction (see Hiramatsu et al.47 in Table 1). This system more accurately reflects a natural HIV infection because Vpr expression is restricted until adulthood and further validates the results from noninducible models.

Therapeutic Testing in the HIVAN Mouse Model

HIVAN mouse models have been used to investigate the potential efficacy of renoprotective therapeutic strategies in managing HIVAN. The angiotensin-converting enzyme inhibitor captopril reduces glomerular and tubulointerstitial pathology when administered to Tg26 (HIVΔgag/pol) mice.48 This result was consistent with the results of two small clinical trials that also showed angiotensin-converting enzyme inhibitor therapy is beneficial in HIVAN.49,50 More recently, the angiotensin II type 1 receptor blocker olmesartan also reduced disease in the inducible podocyte-specific Vpr murine HIVAN model.47 Conversely, administration of angiotensin II in this same model exacerbated progression of the disease.51 This effect was independent of angiotensin II or olmesartan's effect on systemic BP because other vasoactive agents (norepinephrine, hydralazine, and azelnidipine) did not have an effect on renal pathology. Taken together, these studies suggest that the murine model seems to be an effective tool in further defining both mechanisms of disease and potential therapeutic interventions.

Rat HIVAN Model

Although the mouse model has been the primary small animal model of HIVAN, a Sprague-Dawley rat model also exists (see Ray et al.52 in Table 1).52,53 The same HIVΔgag/pol transgene driven by the viral LTR promoter in the Tg26 mouse model has been used to create a rat HIVAN model. Renal manifestations in these rats range from mild to severe and show the characteristic aspects of HIVAN pathology. The kidneys are grossly enlarged and diffusely pale and have a pitted appearance. Microcystic change, glomerular sclerosis, tubular cell proliferation, and visceral epithelial cell enlargement all are observed. In addition, the rat HIVAN model shows prominent mesangial hyperplasia with an increase in both glomerular and tubular basic fibroblast growth factor staining.53 One potential advantage of the rat model is that the HIV transgene seems to be more widely and efficiently expressed in rats than mice, perhaps indicating a improved functionality of HIV-1 tat, the viral transactivator.

Simian Immunodeficiency Virus and Feline Immunodeficiency Virus: Natural Models of Lentivirus-Induced Renal Disease

Simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV) are lentiviruses closely related to HIV. In both instances, host infection can result in nephropathy.

Primates infected with SIV or a chimeric SHIV also develop renal insufficiency resembling aspects of both HIVAN and hemolytic uremic syndrome. In an early study, one of three rhesus macaques and one of three pig-tailed macaques each intravenously infected with the SIV isolate SIV/Mne developed renal disease including FSGS, tubular necrosis, and interstitial inflammation (see Benveniste et al.54 in Table 2). Another study followed rhesus and pig-tailed macaques infected with different SHIV strains (SHIV KU-1, SHIV KU-2, and SHIV KU-MC4) that were derived from passaging the nonpathogenic SHIV-4 clone in vivo. Here, varying degrees of renal disease severity were also observed (see Stephens et al.55 in Table 2). Subsequent characterization of the most pathogenic clone, SHIV KU2-MC4, found that it had a newly acquired tropism to macrophages compared to the parent strain.56 Two other studies have examined the role of viral tropism in renal disease development. Five of seven rhesus macaques intravenously inoculated with a macrophage-tropic form of SIV (SIVmacR71/17E) developed FSGS and also showed mild microcystic dilation and lymphocyte infiltration (see Stephens et al.57 in Table 2). In another study, six rhesus macaques were inoculated with a lymphocyte-tropic form of SIV (SIVmac239; see Gattone et al.58 in Table 2). Glomerulosclerosis (two of six primates), mesangial hyperplasia (three of six), and tubulointerstitial inflammation (five of six) all were observed. When SIV env gp120 sequences were recovered from the glomeruli of diseased primates, they had evolved to a macrophage-tropic phenotype. These results indicated that selective pressure is exerted in the glomerulus. Studying viral tropism and evolution is a major advantage of the primate model over the transgenic murine models that are incapable of probing this aspect of HIVAN.

View this table:
Table 2.

Summary of nine infectious HIVAN models that are discussed in this reviewa

FIV infects both domestic and feral felines, causing an AIDS-like illness. In addition, FIV-related renal disease has been reported. In one study, glomerulosclerosis, tubulointerstitial disease, and/or mesangial widening with IgM, C3, and mild IgG deposition was observed in 12 of 15 FIV+ felines (see Poli et al.59 in Table 2). A subsequent study demonstrated direct FIV infection of the tubular epithelium by p24 immunostaining and PCR suggesting a similar pathogenesis as HIVAN60; however, because FIV has no functional homolog to HIV-1 Vpr and Nef, the primary culprits in HIVAN, the mechanism is likely different. A possible explanation is that the FIV Vif gene may be fulfilling HIV-1 Vpr's role of impairing cell division. Recent studies of HIV have shown that gene deletions of both Vpr and Vif are required to completely prevent G2 “stalling” (a process in between complete G2 arrest and normal cell-cycle progression), but the mechanism is unknown.61,62

Conclusions

The pathogenesis of HIVAN is a multifactorial process whereby genetic susceptibility, host response, and viral factors are important contributors. Animal models have provided a valuable research tool to study each aspect of pathogenesis. They have shown that intracellular renal expression of HIV is both sufficient and required to cause HIVAN in a genetically susceptible host. Tissue-specific models have further defined the role of HIV infection of individual renal compartments. Single HIV gene or gene deletion transgenic models have defined HIV-1 Nef and Vpr as the major disease contributors. In addition, small animal models have been used to test therapeutic efficacy. Last, whereas murine transgenic models are nonreplicative and applicable only to post–HIV entry events, primate models of SIV-associated nephropathy provide some insight into the role of viral evolution.

Disclosures

None.

Acknowledgments

We thank Christina Wyatt and Justin Chan for contributions and critical review.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

References

  1. 1.↵
    1. Rao T,
    2. Filippone E,
    3. Nicastri A,
    4. Landesman SH,
    5. Frank E,
    6. Chen CK,
    7. Friedman EA
    : Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 310: 669–673, 1984
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Shahinian V,
    2. Rajaraman S,
    3. Borucki M,
    4. Grady J,
    5. Hollander WM,
    6. Ahuja TS
    : Prevalence of HIV associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis 35: 884–888, 2000
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Ahuja TS,
    2. Borucki M,
    3. Funtanilla M,
    4. Shahinian V,
    5. Hollander M,
    6. Rajaraman S
    : Is the prevalence of HIV-associated nephropathy decreasing? Am J Nephrol 19: 655–659, 1999
    OpenUrlCrossRefPubMed
  4. 4.↵
    Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, Department of Health and Human Services, November 3, 2008; 1–139. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed November 2008
  5. 5.↵
    1. Gupta SK,
    2. Eustace JA,
    3. Winston JA,
    4. Boydstun II.,
    5. Ahuja TS,
    6. Rodriguez RA,
    7. Tashima KT,
    8. Roland M,
    9. Franceschini N,
    10. Palella FJ,
    11. Lennox JL,
    12. Klotman PE,
    13. Nachman SA,
    14. Hall SD,
    15. Szczech LA
    : Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 40: 1559–1585, 2005
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. D'Agati V,
    2. Appel GB
    : HIV infection and the kidney. J Am Soc Nephrol 8: 138–152, 1997
    OpenUrlAbstract
  7. 7.↵
    1. Rao TK,
    2. Friedman EA,
    3. Nicastri AD
    : The types of renal disease in the acquired immunodeficiency syndrome. N Engl J Med 316: 1062–1068, 1987
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Laradi A,
    2. Mallet A,
    3. Beaufils H,
    4. Allouache M,
    5. Martinez F
    : HIV-associated nephropathy: Outcome and prognosis factors. J Am Soc Nephrol 9: 2327–2335, 1998
    OpenUrlAbstract
  9. 9.↵
    1. Carbone L,
    2. D'Agati V,
    3. Cheng JT,
    4. Appel GB
    : Course and prognosis of human immunodeficiency virus-associated nephropathy. Am J Med 87: 389–395, 1989
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Bourgoignie JJ,
    2. Meneses R,
    3. Ortiz C,
    4. Jaffe D,
    5. Pardo V
    : The clinical spectrum of renal disease associated with human immunodeficiency virus. Am J Kidney Dis 12: 131–137, 1988
    OpenUrlPubMed
  11. 11.↵
    1. D'Agati V,
    2. Suh JI,
    3. Carbone L,
    4. Cheng JT,
    5. Appel G
    : Pathology of HIV-associated nephropathy: A detailed morphologic and comparative study. Kidney Int 35: 1358–1370, 1989
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Ross MJ,
    2. Bruggeman LA,
    3. Wilson PD,
    4. Klotman PE
    : Microcyst formation and HIV-1 gene expression occur in multiple nephron segments in HIV-associated nephropathy. J Am Soc Nephrol 12: 2645–2651, 2001
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Lu TC,
    2. Ross MJ
    : HIV associated nephropathy: A brief review. Mt Sinai J Med 72: 193–199, 2005
    OpenUrlPubMed
  14. 14.↵
    1. Barisoni L,
    2. Kriz W,
    3. Mundel P,
    4. D'Agati V
    : The dysregulated podocyte phenotype: A novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 10: 51–61, 1999
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Bariety J,
    2. Nochy D,
    3. Mandet C,
    4. Jacquot C,
    5. Glotz D,
    6. Meyrier A
    : Podocytes undergo phenotypic changes and express macrophagic-associated markers in idiopathic collapsing glomerulopathy. Kidney Int 53: 918–925, 1998
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Barisoni L,
    2. Mokrzycki M,
    3. Sablay L,
    4. Nagata M,
    5. Yamase H,
    6. Mundel P
    : Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies. Kidney Int 58: 137–143, 2000
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Shankland SJ,
    2. Eitner F,
    3. Hudkins KL,
    4. Goodpaster T,
    5. D'Agati V,
    6. Alpers CE
    : Differential expression of cyclin-dependent kinase inhibitors in human glomerular disease: Role in podocyte proliferation and maturation. Kidney Int 58: 674–683, 2000
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Barisoni L,
    2. Bruggeman L,
    3. Mundel P,
    4. D'Agati VD,
    5. Klotman PE
    : HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney Int 58: 173–181, 2000
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Dickie P,
    2. Felser J,
    3. Eckhaus M,
    4. Bryant J,
    5. Silver J,
    6. Marinos N,
    7. Notkins AL
    : HIV-associated nephropathy in transgenic mice expressing HIV-1 genes. Virology 185: 109–119, 1991
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Bruggeman LA,
    2. Thomson MM,
    3. Nelson PJ,
    4. Kopp JB,
    5. Rappaport J,
    6. Klotman PE,
    7. Klotman ME
    : Patterns of HIV-1 mRNA expression in transgenic mice are tissue-dependent. Virology 202: 940–948, 1994
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Kopp J,
    2. Klotman M,
    3. Adler S,
    4. Bruggeman LA,
    5. Dickie P,
    6. Marinos NJ,
    7. Eckhaus M,
    8. Bryant JL,
    9. Notkins AL,
    10. Klotman PE
    : Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type I genes. Proc Natl Acad Sci U S A 89: 1577–1581, 1992
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Bruggeman L,
    2. Dikman S,
    3. Meng C,
    4. Quaggin SE,
    5. Coffman TM,
    6. Klotman PE
    : Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J Clin Invest 100: 84–92, 1997
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Bruggeman LA,
    2. Ross MD,
    3. Tanji N,
    4. Cara A,
    5. Dikman S,
    6. Gordon RE,
    7. Burns GC,
    8. D'Agati VD,
    9. Winston JA,
    10. Klotman ME,
    11. Klotman PE
    : Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol 11: 2079–2087, 2000
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Rosenstiel PE,
    2. Gruosso T,
    3. Letourneau AM,
    4. Chan JJ,
    5. LeBlanc A,
    6. Husain M,
    7. Najfeld V,
    8. Planelles V,
    9. D'Agati VD,
    10. Klotman ME,
    11. Klotman PE
    : HIV-1 Vpr inhibits cytokinesis in human renal proximal tubule cells. Kidney Int 74: 1049–1058, 2008
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Conaldi PG,
    2. Biancone L,
    3. Bottelli A,
    4. Wade-Evans A,
    5. Racusen LC,
    6. Boccellino M,
    7. Orlandi V,
    8. Serra C,
    9. Camussi G,
    10. Toniolo A
    : HIV-1 kills renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas upregulation. J Clin Invest 102: 2041–2049, 1998
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Ross MJ,
    2. Martinka S,
    3. D'Agati VD,
    4. Bruggeman LA
    : NF-kappaB regulates Fas-mediated apoptosis in HIV-associated nephropathy. J Am Soc Nephrol 16: 2403–2411, 2005
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Ross MJ,
    2. Wosnitzer MS,
    3. Ross MD,
    4. Granelli B,
    5. Gusella GL,
    6. Husain M,
    7. Kaufman L,
    8. Vasievich M,
    9. D'Agati VD,
    10. Wilson PD,
    11. Klotman ME,
    12. Klotman PE
    : Role of ubiquitin-like protein FAT10 in epithelial apoptosis in renal disease. J Am Soc Nephrol 17: 996–1004, 2006
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Ross MD,
    2. Bruggeman LA,
    3. Hanss B,
    4. Sunamoto M,
    5. Marras D,
    6. Klotman ME,
    7. Klotman PE
    : Podecan, a novel small leucine-rich repeat protein expressed in the sclerotic glomerular lesion of experimental HIV-associated nephropathy. J Biol Chem 278: 33248–33255, 2003
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Mundel P,
    2. Reiser J,
    3. Zuniga Mejia Borja A,
    4. Pavenstadt H,
    5. Davidson GR,
    6. Kriz W,
    7. Zeller R
    : Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines. Exp Cell Res 236: 248–258, 1997
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Gharavi A,
    2. Ahmad T,
    3. Wong R,
    4. Hooshyar R,
    5. Vaughn J,
    6. Oller S,
    7. Frankel RZ,
    8. Bruggeman LA,
    9. D'Agati VD,
    10. Klotman PE,
    11. Lifton RP
    : Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3. Proc Natl Acad Sci U S A 101: 2488–2493, 2004
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Chan KT,
    2. Papeta N,
    3. Martino J,
    4. Zheng Z,
    5. Frankel R,
    6. Klotman PE,
    7. D'Agati VD,
    8. Lifton RP,
    9. Gharavi A
    : Accelerated development of collapsing glomerulopathy in mice congenic for the HIVAN1 locus on chr 3A1–A3. Kidney Int 75: 366–372, 2009
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Kopp JB,
    2. Smith MW,
    3. Nelson GW,
    4. Johnson RC,
    5. Freedman BI,
    6. Bowden DW,
    7. Oleksyk T,
    8. McKenzie LM,
    9. Kajiyama H,
    10. Ahuja TS,
    11. Berns JS,
    12. Briggs W,
    13. Cho ME,
    14. Dart RA,
    15. Kimmel PL,
    16. Korbet SM,
    17. Michel DM,
    18. Mokrzycki MH,
    19. Schelling JR,
    20. Simon E,
    21. Trachtman H,
    22. Vlahov D,
    23. Winkler CA
    : MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40: 1175–1184, 2008
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Kao WH,
    2. Klag MJ,
    3. Meoni LA,
    4. Reich D,
    5. Berthier-Schaad Y,
    6. Li M,
    7. Coresh J,
    8. Patterson N,
    9. Tandon A,
    10. Powe NR,
    11. Fink NE,
    12. Sadler JH,
    13. Weir MR,
    14. Abboud HE,
    15. Adler SG,
    16. Divers J,
    17. Iyengar SK,
    18. Freedman BI,
    19. Kimmel PL,
    20. Knowler WC,
    21. Kohn OF,
    22. Kramp K,
    23. Leehey DJ,
    24. Nicholas SB,
    25. Pahl MV,
    26. Schelling JR,
    27. Sedor JR,
    28. Thornley-Brown D,
    29. Winkler CA,
    30. Smith MW,
    31. Parekh RS
    Family Investigation of Nephropathy and Diabetes Research Group: MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40: 1185–1192, 2008
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Hanna Z,
    2. Kay D,
    3. Cool M,
    4. Jothy S,
    5. Rebai N,
    6. Jolicoeur P
    : Transgenic mice expressing human immunodeficiency virus type 1 in immune cells develop a severe AIDS-like disease. J Virol 72: 121–132, 1998
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Hanna Z,
    2. Weng X,
    3. Kay D,
    4. Poudrier J,
    5. Lowell C,
    6. Jolicoeur P
    : The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck. J Virol 75: 9378–9392, 2001
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Hanna Z,
    2. Priceputu E,
    3. Kay DG,
    4. Poudrier J,
    5. Chrobak P,
    6. Jolicoeur P
    : In vivo mutational analysis of the N-terminal region of HIV-1 Nef reveals critical motifs for the development of an AIDS-like disease in CD4C/HIV transgenic mice. Virol 327: 273–286, 2004
    OpenUrlCrossRef
  37. 37.↵
    1. Hanna Z,
    2. Kay D,
    3. Rebai N,
    4. Guimond A,
    5. Jothy S,
    6. Jolicoeur P
    : Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95: 163–175, 1998
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Husain M,
    2. D'Agati V,
    3. He J,
    4. Klotman ME,
    5. Klotman PE
    : HIV-1 Nef induces dedifferentiation of podocytes in vivo: A characteristic feature of HIVAN. AIDS 19: 1975–1980, 2005
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Husain M,
    2. Gusella GL,
    3. Klotman ME,
    4. Gelman IH,
    5. Ross MD,
    6. Schwartz EJ,
    7. Cara A,
    8. Klotman PE
    : HIV-1 Nef induces proliferation and anchorage-independent growth in podocytes. J Am Soc Nephrol 13: 1806–1815, 2002
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. He JC,
    2. Husain M,
    3. Sunamoto M,
    4. D'Agati VD,
    5. Klotman ME,
    6. Iyengar R,
    7. Klotman PE
    : Nef stimulates proliferation of glomerular podocytes through activation of Src dependent Stat3 and MAPK1,2 pathways. J Clin Invest 114: 643–651, 2004
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Zhong J,
    2. Zuo Y,
    3. Ma J,
    4. Fogo AB,
    5. Jolicoeur P,
    6. Ichikawa I,
    7. Matsusaka T
    : Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int 68: 1048–1060, 2005
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Appel D,
    2. Kershaw DB,
    3. Smeets B,
    4. Yuan G,
    5. Fuss A,
    6. Frye B,
    7. Elger M,
    8. Kriz W,
    9. Floege J,
    10. Moeller MJ
    : Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 20: 333–343, 2009
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Kajiyama W,
    2. Kopp J,
    3. Marinos N,
    4. Klotman PE,
    5. Dickie P
    : Glomerulosclerosis and viral gene expression in HIV-transgenic mice: Role of nef. Kidney Int 58: 1148–1159, 2000
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Dickie P,
    2. Ramsdell F,
    3. Notkins AL,
    4. Venkatesan S
    : Spontaneous and inducible epidermal hyperplasia in transgenic mice expressing HIV-1 Nef. Virology 197: 431–438, 1993
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Dickie P,
    2. Roberts A,
    3. Uwiera R,
    4. Witmer J,
    5. Sharma K,
    6. Kopp J
    : Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV associated nephropathy. Virology 322: 69–81, 2004
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Zuo Y,
    2. Matsusaka T,
    3. Zhong J,
    4. Ma J,
    5. Ma LJ,
    6. Hanna Z,
    7. Jolicoeur P,
    8. Fogo AB,
    9. Ichikawa I
    : HIV-1 genes Vpr and Nef synergistically damage podocytes leading to glomerulosclerosis. J Am Soc Nephrol 17: 2832–2843, 2006
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Hiramatsu N,
    2. Hiromura K,
    3. Shigehara T,
    4. Kuroiwa T,
    5. Ideura H,
    6. Sakurai N,
    7. Takeuchi S,
    8. Tomioka M,
    9. Ikeuchi H,
    10. Kaneko Y,
    11. Ueki K,
    12. Kopp JB,
    13. Nojima Y
    : Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. J Am Soc Nephrol 18: 515–527, 2007
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Bird JE,
    2. Durham SK,
    3. Giancarli MR,
    4. Gitlitz PH,
    5. Pandya DG,
    6. Dambach DM,
    7. Mozes MM,
    8. Kopp JB
    : Captopril prevents nephropathy in HIV-transgenic mice. J Am Soc Nephrol 9: 1441–1447, 1998
    OpenUrlAbstract
  49. 49.↵
    1. Kimmel PL,
    2. Mishkin G,
    3. Umana W
    : Captopril and renal survival in patients with human immunodeficiency virus nephropathy. Am J Kidney Dis 28: 202–208, 1996
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. Burns GC,
    2. Paul SK,
    3. Toth IR,
    4. Sivak SL
    : Effect of angiotensin-converting enzyme inhibition in HIV-associated nephropathy. J Am Soc Nephrol 8: 1 140–1 146, 1997
    OpenUrlAbstract
  51. 51.↵
    1. Ideura H,
    2. Hiromura K,
    3. Hiramatsu N,
    4. Shigehara T,
    5. Takeuchi S,
    6. Tomioka M,
    7. Sakairi T,
    8. Yamashita S,
    9. Maeshima A,
    10. Kaneko Y,
    11. Kuroiwa T,
    12. Kopp JB,
    13. Nojima Y
    : Angiotensin II provokes podocyte injury in murine model of HIV-associated nephropathy. Am J Physiol Renal Physiol 293: F1214–F1221, 2007
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Reid W,
    2. Sadowska M,
    3. Denaro F,
    4. Rao S,
    5. Foulke J Jr.,
    6. Hayes N,
    7. Jones O,
    8. Doodnauth D,
    9. Davis H,
    10. Sill A,
    11. O'Driscoll P,
    12. Huso D,
    13. Fouts T,
    14. Lewis G,
    15. Hill M,
    16. Kamin-Lewis R,
    17. Wei C,
    18. Ray P,
    19. Gallo RC,
    20. Reitz M,
    21. Bryant J
    : An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc Natl Acad Sci U S A 98: 9271–9276, 2001
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Ray P,
    2. Liu X,
    3. Robinson L,
    4. Reid W,
    5. Xu L,
    6. Owens JW,
    7. Jones OD,
    8. Denaro F,
    9. Davis HG,
    10. Bryant JL
    : A novel HIV-1 transgenic rat model of childhood HIV-1 associated nephropathy. Kidney Int 63: 2242–2253, 2003
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Benveniste R,
    2. Morton W,
    3. Clark E,
    4. Tsai CC,
    5. Ochs HD,
    6. Ward JM,
    7. Kuller L,
    8. Knott WB,
    9. Hill RW,
    10. Gale MJ,
    11. et al.
    : Inoculation of baboons and macaques with simian immunodeficiency virus/Mne, a primate lentivirus closely related to human immunodeficiency virus type 2. J Virol 62: 2091–2101, 1988
    OpenUrlAbstract/FREE Full Text
  55. 55.↵
    1. Stephens EB,
    2. Tian C,
    3. Dalton SB,
    4. Gattone V
    : Simian-human immunodeficiency virus-associated nephropathy in macaques. AIDS Res Hum Retroviruses 16: 1295–1306, 2000
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Liu ZQ,
    2. Muhkerjee S,
    3. Sahni M,
    4. McCormick-Davis C,
    5. Leung K,
    6. Li Z,
    7. Gattone VH 2nd.,
    8. Tian C,
    9. Doms RW,
    10. Hoffman TL,
    11. Raghavan R,
    12. Narayan O,
    13. Stephens EB
    : Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques. Virol 260: 295–307, 1999
    OpenUrlCrossRef
  57. 57.↵
    1. Stephens E,
    2. Tian C,
    3. Li Z,
    4. Narayan O,
    5. Gattone VH 2nd.
    : Rhesus macaques infected with macrophage tropic simian immunodeficiency virus (SIVmacR71/17E) exhibit extensive focal segmental and global glomerulosclerosis. J Virol 72: 8820–8832, 1998
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    1. Gattone V,
    2. Tian C,
    3. Zhuge W,
    4. Sahni M,
    5. Narayan O,
    6. Stephens EB
    : SIV-associated nephropathy in rhesus macaques infected with lymphocyte-tropic SIVmac239. AIDS Res Hum Retroviruses 14: 1168–1180, 1998
    OpenUrl
  59. 59.↵
    1. Poli A,
    2. Abramo F,
    3. Taccini E,
    4. Guidi G,
    5. Barsotti P,
    6. Bendinelli M,
    7. Malvaldi G
    : Renal involvement in feline immunodeficiency virus infection: A clinicopathological study. Nephron 64: 282–288, 1993
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Poli A,
    2. Abramo F,
    3. Matteucci D,
    4. Baldinotti F,
    5. Pistello M,
    6. Lombardi S,
    7. Barsotti P,
    8. Bendinelli M
    : Renal involvement in feline immunodeficiency virus infection: p24 antigen detection, virus isolation and PCR analysis. Vet Immunol Immunopathol 46: 13–20, 1995
    OpenUrlCrossRefPubMed
  61. 61.↵
    1. Wang JF,
    2. Shackelford JM,
    3. Casella CR,
    4. Shivers DK,
    5. Rapaport EL,
    6. Liu B,
    7. Yu XF,
    8. Finkel TH
    : The Vif accessory protein alters the cell cycle of human immunodeficiency virus type 1 infected cells. Virology 359: 243–252, 2007
    OpenUrlCrossRefPubMed
  62. 62.↵
    1. Sakai K,
    2. Dimas J,
    3. Lenardo MJ
    : The Vif and Vpr accessory proteins independently cause HIV-1-induced T cell cytopathicity and cell cycle arrest. Proc Natal Acad Sci U S A 103: 3369–3374, 2006
    OpenUrlAbstract/FREE Full Text
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Transgenic and Infectious Animal Models of HIV-Associated Nephropathy
Paul Rosenstiel, Ali Gharavi, Vivette D'Agati, Paul Klotman
JASN Nov 2009, 20 (11) 2296-2304; DOI: 10.1681/ASN.2008121230
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