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AIDS (London, England) Sep 2020HIV-1 can infect and persist in different organs and tissues, resulting in the generation of multiple viral compartments and reservoirs. Increasing evidence supports the...
OBJECTIVES
HIV-1 can infect and persist in different organs and tissues, resulting in the generation of multiple viral compartments and reservoirs. Increasing evidence supports the kidney as such a reservoir. Previous work demonstrated that HIV-1 infected CD4 T-cells transfer virus to renal tubule epithelial (RTE) cells through cell-to-cell contact. In addition to CD4 T cells, macrophages represent the other major target of HIV-1. Renal macrophages induce and regulate inflammatory responses and are critical to homeostatic regulation of the kidney environment. Combined with their ability to harbour virus, macrophages may also play an important role in the spread of HIV-1 infection in the kidney.
DESIGN AND METHODS
Multiparametric histochemistry analysis was performed on kidney biopsies from individuals with HIV-1 associated nephropathy (HIVAN). Primary monocyte-derived macrophages were infected with a GFP-expressing replication competent HIV-1. HIV-1 transfer from macrophages to RTE cells was carried out in a coculture system and evaluated by fluorescence-microscopy and flow-cytometry. Live imaging was performed to assess the fate of HIV-1 infected RTE cells over time.
RESULTS
We show that macrophages are abundantly present in the renal inflammatory infiltrate of individuals with HIVAN. We observed contact-dependent HIV-1 transfer from infected macrophages to both primary and immortalized renal cells. Live imaging of HIV-1 infected RTE cells revealed four different fates: proliferation, hypertrophy, latency and cell death.
CONCLUSION
Our study suggests that macrophages may play a role in the dissemination of HIV-1 in the kidney and that proliferation of infected renal cells may contribute to HIV-1 persistence in this compartment.
Topics: AIDS-Associated Nephropathy; CD4-Positive T-Lymphocytes; Cell Proliferation; Epithelial Cells; HIV Infections; Humans; Kidney; Kidney Tubules; Macrophages; Retrospective Studies; Virus Latency; Virus Replication
PubMed: 32701578
DOI: 10.1097/QAD.0000000000002589 -
Disease Models & Mechanisms Dec 2019Notch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various...
Notch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various renal cells in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) patients and rodent models of HIVAN. In this study, we examined whether the Notch pathway can be distinctly activated by HIV-1 gene products and whether Notch4, in particular, can influence disease progression. Using luciferase reporter assays, we did not observe activation of the promoter with the HIV protein Nef in podocytes. Further, we observed upregulated expression of a gamma secretase complex protein, presenilin 1, but not Notch4, in podocytes infected with an HIV-1 expression construct. To assess the effects of Notch4 on HIVAN disease progression, we engineered Tg26 mice with global deletion of the Notch4 intracellular domain ( ), which is required for signaling function. These mice ( ) showed a significant improvement in renal function and a significant decrease in mortality compared to Tg26 mice. Histological examination of kidneys showed that mice had overall glomerular, tubulointerstitial injury and a marked decrease in interstitial inflammation. A significant decrease in the proliferating cells was observed in the tubulointerstitial compartments of mice. Consistent with the diminished inflammation, kidneys from mice also showed a significant decrease in expression of the inflammatory cytokine transcripts and , as well as the master inflammatory transcription factor NF-κB ( transcripts and p65 protein). These data identify Notch4 as an important mediator of tubulointerstitial injury and inflammation in HIVAN and a potential therapeutic target.
Topics: AIDS-Associated Nephropathy; Animals; Cell Proliferation; Crosses, Genetic; Disease Models, Animal; Disease Progression; Female; Gene Deletion; HEK293 Cells; Humans; Inflammation; Kidney; Male; Mice; Mice, Transgenic; NF-kappa B p50 Subunit; Podocytes; Receptor, Notch4; Signal Transduction; Transcription Factor RelA; Treatment Outcome; nef Gene Products, Human Immunodeficiency Virus
PubMed: 31727625
DOI: 10.1242/dmm.040642 -
Scientific Reports Nov 2019HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral...
HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral genes, including vpr. Antiretroviral therapy ameliorates HIVAN without eradicating HIV from the kidneys and the mechanism by which it protects kidneys is poorly understood. Since HIV protease inhibitors have "off target" cellular effects, we studied whether darunavir, the most commonly prescribed protease inhibitor, protects kidneys from HIV-induced injury via mechanisms independent of HIV protease and viral replication. Renal epithelial cells were transduced with lentiviruses encoding HIV (lacking protease and reverse transcriptase), Vpr, or vector control. Darunavir attenuated HIV and Vpr-induced activation of Stat3, Src, Erk, and cytokines, which are critical for HIVAN pathogenesis. We then studied HIV-transgenic mice, which develop HIVAN in the absence of HIV protease or reverse transcriptase. Mice were treated with darunavir, zidovudine, darunavir + zidovudine, or control. Darunavir and darunavir + zidovudine reduced albuminuria and histologic kidney injury and normalized expression of dysregulated proteins. RNA-seq analyses demonstrated that darunavir suppressed HIV-induced upregulation of immune response genes in human kidney cells. These data demonstrate that darunavir protects against HIV-induced renal injury via mechanisms that are independent of inhibition of HIV protease.
Topics: AIDS-Associated Nephropathy; Animals; Cell Line; Darunavir; HIV Protease Inhibitors; HIV-1; Humans; Kidney; MAP Kinase Signaling System; Mice; Mice, Transgenic; Zidovudine
PubMed: 31676833
DOI: 10.1038/s41598-019-52278-3 -
Journal of Infection in Developing... Sep 2020End-stage renal disease (ESRD) related to HIV is becoming a leading cause of renal replacement therapy requirement is some areas of the world. Our study aims to describe...
INTRODUCTION
End-stage renal disease (ESRD) related to HIV is becoming a leading cause of renal replacement therapy requirement is some areas of the world. Our study aims to describe the incidence and renal outcomes of HIV-associated nephropathy (HIVAN), and immune-mediated kidney disease related to HIV (HIVICK) in Colombia.
METHODOLOGY
A retrospective cohort study was performed, including all HIVAN or HIVICK incident cases assessed by the infectious diseases division in a high complexity institution in Colombia, between 2004 and 2018. A longitudinal data model under the Generalized Estimating Equations (GEE) method was used to determine changes on the glomerular filtration rate (GFR) over time.
RESULTS
Within a cohort composed by 1509 HIV-infected patients, we identified 22 with HIV-associated glomerular disease. Cumulative incidence was 1.45%. At diagnosis, GFR was above 30 mL/min in 90.8% of patients, and 77.2% displayed sub-nephrotic proteinuria. Factors associated with GFR at diagnosis were: level of CD4 (Coefficient 0.113, CI 95 %: 0.046, 0.179, p < 0.01), and the inverse of the CD4/CD8 ratio. The GEE model did not demonstrate significant changes in the GFR over a 3-year period. Findings were similar when comparing GFR at diagnosis with GFR at 12 (-3.9 mL/min/1.73m2, CI 95% -7.3, 0.4, p = 0.98), 24 (-2.47 mL/min/1.73m2, CI 95% -7.0, 2.1, p=0.85), and 36 months (0.39 mL/min/1.73m2, CI 95% -4.4, 5.2, p = 0.43) of follow-up.
CONCLUSIONS
Patients with glomerular disease associated with HIV have stable GFR over a 3-year period, and low rates of progression towards dialysis requirement. Differences with previous reports could be related with early diagnosis and treatment with highly active antiretroviral therapy.
Topics: AIDS-Associated Nephropathy; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-CD8 Ratio; Colombia; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Kidney Failure, Chronic; Longitudinal Studies; Male; Middle Aged; Retrospective Studies
PubMed: 33031092
DOI: 10.3855/jidc.12030 -
Nephrology, Dialysis, Transplantation :... Feb 2021Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney...
BACKGROUND
Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney diseases, HIV-associated nephropathy (HIVAN) is a rapidly progressive renal disease characterized by collapsing focal glomerulosclerosis (GS), microcystic tubular dilation, interstitial inflammation and fibrosis. Although the incidence of end-stage renal disease due to HIVAN has dramatically decreased with the widespread use of antiretroviral therapy, the prevalence of CKD continues to increase in HIV-positive individuals. Recent studies have highlighted the role of apoptosis signal-regulating kinase 1 (ASK1) in driving kidney disease progression through the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase and selective ASK-1 inhibitor GS-444217 was recently shown to reduce kidney injury and disease progression in various experimental models. Therefore we examined the efficacy of ASK1 antagonism by GS-444217 in the attenuation of HIVAN in Tg26 mice.
METHODS
GS-444217-supplemented rodent chow was administered in Tg26 mice at 4 weeks of age when mild GS and proteinuria were already established. After 6 weeks of treatment, the kidney function assessment and histological analyses were performed and compared between age- and gender-matched control Tg26 and GS-444217-treated Tg26 mice.
RESULTS
GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function. Taken together, GS-4442217 attenuated the full spectrum of HIVAN pathology in Tg26 mice.
CONCLUSIONS
ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN.
Topics: AIDS-Associated Nephropathy; Animals; Disease Models, Animal; Fibrosis; Inflammation; MAP Kinase Kinase Kinase 5; Mice; Mice, Transgenic; Protein Kinase Inhibitors; Proteinuria
PubMed: 33097961
DOI: 10.1093/ndt/gfaa198 -
Disease Models & Mechanisms Aug 2021People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding...
People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease. Disease risk follows a recessive mode of inheritance, which is puzzling given the considerable data that G1 and G2 are toxic gain-of-function variants. We developed coisogenic bacterial artificial chromosome (BAC) transgenic mice harboring either the wild-type (G0), G1 or G2 forms of human APOL1. Expression of interferon gamma (IFN-γ) via plasmid tail vein injection results in upregulation of APOL1 protein levels together with robust induction of heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 mice. The disease phenotype was greater in G2/G2 mice. Neither heterozygous (G1/G0 or G2/G0) risk variant mice nor hemizygous (G1/-, G2/-) mice had significant kidney injury in response to IFN-γ, although the heterozygous mice had a greater proteinuric response than the hemizygous mice, suggesting that the lack of significant disease in humans heterozygous for G1 or G2 is not due to G0 rescue of G1 or G2 toxicity. Studies using additional mice (multicopy G2 and a non-isogenic G0 mouse) supported the notion that disease is largely a function of the level of risk variant APOL1 expression. Together, these findings shed light on the recessive nature of APOL1-nephropathy and present an important model for future studies.
Topics: AIDS-Associated Nephropathy; Animals; Apolipoprotein L1; Chromosomes, Artificial, Bacterial; Gain of Function Mutation; Genetic Predisposition to Disease; Humans; Mice; Mice, Transgenic
PubMed: 34350953
DOI: 10.1242/dmm.048952 -
PloS One 2022HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has...
HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na+-Cl- cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.
Topics: Aldosterone; Animals; Chlorocebus aethiops; Gene Products, vpr; HIV-1; Kidney Tubules, Distal; Mice; Mice, Transgenic; Phosphoenolpyruvate; RNA, Messenger; Receptors, Mineralocorticoid; Renin; Sodium; Sodium Chloride; Sodium Chloride Symporters; Solute Carrier Family 12, Member 3; Thiazides
PubMed: 36129874
DOI: 10.1371/journal.pone.0273313 -
AIDS Research and Human Retroviruses Aug 2021Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 is responsible for a new coronavirus disease known as coronavirus disease-19 (COVID-19). SARS-CoV-2 reports... (Review)
Review
Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 is responsible for a new coronavirus disease known as coronavirus disease-19 (COVID-19). SARS-CoV-2 reports neurotropic properties and may have neurological implications, and this creates another health burden for people living with HIV. As yet, the impact of COVID-19 on (neuro)inflammation and the development of HIV-associated neurocognitive disorders (HAND) is not fully known. Here, we reviewed preliminary evidence that provides clues that COVID-19 may exacerbate inflammatory mechanisms related to the development of HAND.
Topics: AIDS-Associated Nephropathy; COVID-19; Humans; Inflammation; Neurocognitive Disorders; SARS-CoV-2
PubMed: 32993321
DOI: 10.1089/AID.2020.0136 -
Journal of Medical Case Reports Dec 2022We present this case of coronavirus disease 2019-associated acute kidney injury with rhabdomyolysis-with noteworthy renal biopsy findings demonstrating myoglobin cast...
BACKGROUND
We present this case of coronavirus disease 2019-associated acute kidney injury with rhabdomyolysis-with noteworthy renal biopsy findings demonstrating myoglobin cast nephropathy-to add to the limited literature on coronavirus disease 2019-related acute kidney injury and rhabdomyolysis.
CASE PRESENTATION
A 67-year-old Caucasian man presented to our hospital with 3 weeks of malaise and decreased oral intake and several days of abnormal taste, poor appetite, decrease urine output, gastrointestinal symptoms, and myalgias, and was ultimately diagnosed with coronavirus disease 2019. His hospital course was complicated by acute kidney injury and, upon workup of his renal failure, was diagnosed with myoglobin cast nephropathy due to coronavirus disease 2019-mediated rhabdomyolysis. Ultimately, his renal function improved following hydration back to his baseline 6 weeks after his initial diagnosis of coronavirus disease 2019.
CONCLUSIONS
Given our limited knowledge of manifestations of coronavirus disease 2019, it is important to have a more in-depth understanding of the spectrum of disease of coronavirus disease 2019, which can affect various organ systems, including the kidney, and the manifestations of end-organ damage associated with it. We present this case to highlight a rarely reported finding of myoglobin cast nephropathy due to coronavirus disease 2019-mediated rhabdomyolysis.
Topics: Male; Humans; Aged; COVID-19; Myoglobin; Rhabdomyolysis; Acute Kidney Injury; Kidney
PubMed: 36578087
DOI: 10.1186/s13256-022-03721-z -
Cureus Feb 2021Human immunodeficiency virus (HIV) infection occurs due to the HIV virus. It results in an immunodeficient state and multi-organ system infections and malignancy known...
Human immunodeficiency virus (HIV) infection occurs due to the HIV virus. It results in an immunodeficient state and multi-organ system infections and malignancy known as AIDS. HIV-associated nephropathy (HIVAN) is the most common HIV kidney involvement and may present as acute kidney injury (AKI), as well as chronic kidney disease (CKD). HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS). HIVAN treatment options include antiretroviral therapy (ART), steroids, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), and hemodialysis (HD). We herein describe the case of a 40-year-old patient with an established diagnosis of HIVAN who has had partial recovery of end-stage renal failure following the initiation of ART.
PubMed: 33717725
DOI: 10.7759/cureus.13181