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Viruses Apr 2022The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system...
The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV-CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir.
Topics: AIDS-Associated Nephropathy; HIV Infections; HIV-1; Humans; Microglia; Organoids; Receptors, HIV
PubMed: 35458559
DOI: 10.3390/v14040829 -
PloS One 2019African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic...
African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Transgene expression, survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice co-expressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups. APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This was absent with APOL1-G2 expression, suggesting APOL1-G2 may have lost this protective function.
Topics: AIDS-Associated Nephropathy; Animals; Apolipoprotein L1; Apolipoproteins; Disease Models, Animal; Genetic Predisposition to Disease; Genetic Variation; Humans; Kidney Glomerulus; Mice; Mice, Inbred BALB C; Mice, Transgenic; Podocytes; Polymorphism, Genetic; Renal Insufficiency, Chronic; Transcriptome
PubMed: 31661509
DOI: 10.1371/journal.pone.0224408 -
Journal of Ultrasound Mar 2018To evaluate the role of kidney echogenicity and morphology in the diagnosis of human immunodeficiency virus-associated nephropathy (HIVAN).
AIM
To evaluate the role of kidney echogenicity and morphology in the diagnosis of human immunodeficiency virus-associated nephropathy (HIVAN).
SUBJECTS AND METHODS
In the cross-sectional study, a sample of 340 anti-retroviral therapy (ART)-naïve AIDS patients underwent laboratory CD4+ count, serum creatinine determination and sonographic renal echogenicity grading and size measurement. Rounded kidneys were described as bulbous while bean-shaped kidneys were described as reniform; echogenicity was categorized into grades 0, 1, 2 and 3. Kidney length, width, thickness and volume were measured in HIVAN and control groups.
RESULTS
Mean age of the population was 42.7 ± 9.4 years; 87.4% had HIVAN. Mean CD4+ count, serum creatinine and GFR for HIVAN patients were 153.1 ± 103.2 cells/mm, 218.4 ± 147.4 mmol/L and 50.1 ± 23.6 mL/min/1.73 m for males and 121.9 ± 91.0 cells/mm, and 222.0 ± 150.4 mmol/L and 39.3 ± 20.6 mL/min/1.73 m for females, respectively; control subjects and non-HIVAN patients had grade 0 renal echogenicity; 56.9% of HIVAN patients had echogenicity grade 3; 5.3% had kidney length < 10 cm; 73.9% had bulbous kidneys; the kidney was significantly wider and thicker in HIVAN (p < 0.05).
CONCLUSION
Sonographic evaluation of renal echogenicity and morphology can reliably predict HIVAN diagnosis. Apathy to screening and late presentation were high while HIV/AIDS remains an important public health problem in the city of Lagos. Unilateral reduction in kidney size could be a major sequela of AIDS while sonographic measurement of absolute kidney length appears inadequate in the evaluation of AIDS patients with nephropathy.
Topics: AIDS-Associated Nephropathy; Adult; Aged; CD4 Lymphocyte Count; Creatinine; Cross-Sectional Studies; Female; HIV Seropositivity; Hospitals, Teaching; Hospitals, University; Humans; Kidney; Male; Middle Aged; Nigeria; Organ Size; Prospective Studies; Severity of Illness Index; Ultrasonography; Young Adult
PubMed: 29374399
DOI: 10.1007/s40477-017-0279-9 -
Disease Models & Mechanisms Jul 2021People of African ancestry living with the human immunodeficiency virus-1 (HIV-1) are at risk of developing HIV-associated nephropathy (HIVAN). Children with HIVAN...
People of African ancestry living with the human immunodeficiency virus-1 (HIV-1) are at risk of developing HIV-associated nephropathy (HIVAN). Children with HIVAN frequently show high plasma fibroblast growth factor-2 (FGF-2) levels; however, the role of circulating FGF-2 in the pathogenesis of childhood HIVAN is unclear. Here, we explored how circulating FGF-2 affected the outcome of HIVAN in young HIV-Tg26 mice. Briefly, we demonstrated that FGF-2 was preferentially recruited in the kidneys of mice without pre-existing kidney disease, precipitating HIVAN by activating phosphorylated extracellular signal-regulated kinase (pERK) in renal epithelial cells, without inducing the expression of HIV-1 genes. Wild-type mice injected with recombinant adenoviral FGF-2 (rAd-FGF-2) vectors carrying a secreted form of human FGF-2 developed transient and reversible HIVAN-like lesions, including proteinuria and glomerular enlargement. HIV-Tg26 mice injected with rAd-FGF-2 vectors developed more-significant proliferative and pro-fibrotic inflammatory lesions, similar to those seen in childhood HIVAN. These lesions were partially reversed by treating mice with the FGF/VEGF receptor tyrosine kinase inhibitor PD173074. These findings suggest that high plasma FGF-2 levels may be an independent risk factor for precipitating HIVAN in young children.
Topics: AIDS-Associated Nephropathy; Animals; Child, Preschool; Disease Models, Animal; Fibroblast Growth Factor 2; HIV-1; Humans; Mice; Mice, Transgenic
PubMed: 34308967
DOI: 10.1242/dmm.048980 -
Refinement of the HIVAN1 Susceptibility Locus on Chr. 3A1-A3 via Generation of Sub-Congenic Strains.PloS One 2016HIV-1 transgenic mice on the FVB/NJ background (TgFVB) represent a validated model of HIV-associated nephropathy (HIVAN). A major susceptibility locus, HIVAN1, was...
HIV-1 transgenic mice on the FVB/NJ background (TgFVB) represent a validated model of HIV-associated nephropathy (HIVAN). A major susceptibility locus, HIVAN1, was previously mapped to chromosome 3A1-A3 in a cross between TgFVB and CAST/EiJ (CAST) strains, and introgression of a 51.9 Mb segment encompassing HIVAN1 from CAST into TgFVB resulted in accelerated development of nephropathy. We generated three sub-congenic strains carrying CAST alleles in the proximal or distal regions of the HIVAN1 locus (Sub-II, 3.02-38.93 Mb; Sub-III, 38.45-55.1 Mb and Sub-IV, 47.7-55.1 Mb, build 38). At 5-10 weeks of age, histologic injury and proteinuria did not differ between HIV-1 transgenic Sub-II and TgFVB mice. In contrast, HIV-1 transgenic Sub-III and Sub-IV mice displayed up to 4.4 fold more histopathologic injury and 6-fold more albuminuria compared to TgFVB mice, similar in severity to the full-length congenic mice. The Sub-IV segment defines a maximal 7.4 Mb interval for HIVAN1, and encodes 31 protein coding genes: 15 genes have missense variants differentiating CAST from FVB, and 14 genes show differential renal expression. Of these, Frem1, Foxo1, and Setd7 have been implicated in the pathogenesis of nephropathy. HIVAN1 congenic kidneys are histologically normal without the HIV-1 transgene, yet their global transcriptome is enriched for molecular signatures of apoptosis, adenoviral infection, as well as genes repressed by histone H3 lysine 27 trimethylation, a histone modification associated with HIV-1 life cycle. These data refine HIVAN1to 7.4 Mb and identify latent molecular derangements that may predispose to nephropathy upon exposure to HIV-1.
Topics: AIDS-Associated Nephropathy; Albuminuria; Animals; Chromosome Mapping; Chromosomes, Human, Pair 3; Crosses, Genetic; Disease Models, Animal; Female; Genetic Loci; Genetic Predisposition to Disease; HIV-1; Humans; Kidney; Male; Mice; Mice, Congenic; Mice, Transgenic
PubMed: 27736906
DOI: 10.1371/journal.pone.0163860 -
Journal of the International... 2022Kidney disease is the fourth most common cause of non-AIDS-related mortality in people living with HIV. Combination antiretroviral therapy (cART) remains the cornerstone...
Kidney disease is the fourth most common cause of non-AIDS-related mortality in people living with HIV. Combination antiretroviral therapy (cART) remains the cornerstone of treatment. However, little is known about the impact of cART on disease outcomes in patients with HIV-associated nephropathy (HIVAN) and HIV-immune complex kidney disease (HIVICK). This systematic review evaluates the impact of cART on progression to end-stage kidney disease (ESKD) and other outcomes in HIV-infected individuals. We conducted a literature search utilizing PubMed, and Cochrane database and 11 articles met inclusion criteria for analysis of which nine HIVAN studies showed decreased progression to ESKD or death for subjects when treated with cART versus those untreated. However, two studies showed no survival advantage with cART. Three HIVICK studies showed improvement in delaying ESKD in subjects on cART compared to untreated subjects. cART appeared to reduce the risk to ESKD or death in patients with both HIVAN and HIVICK.
Topics: AIDS-Associated Nephropathy; HIV Infections; Humans
PubMed: 35369795
DOI: 10.1177/23259582221089194 -
Human Gene Therapy Apr 2020Chronic pain is long-lasting nociceptive state, impairing the patient's quality of life. Existing analgesics are generally not effective in the treatment of chronic... (Review)
Review
Chronic pain is long-lasting nociceptive state, impairing the patient's quality of life. Existing analgesics are generally not effective in the treatment of chronic pain, some of which such as opioids have the risk of tolerance/dependence and overdose death with higher daily opioid doses for increasing analgesic effect. Opioid use disorders have already reached an epidemic level in the United States; therefore, nonopioid analgesic approach and/or use of nonpharmacologic interventions will be employed with increasing frequency. Viral vector-mediated gene therapy is promising in clinical trials in the nervous system diseases. Glutamic acid decarboxylase (GAD) enzyme, a key enzyme in biosynthesis of γ-aminobutyric acid (GABA), plays an important role in analgesic mechanism. In the literature review, we used PubMed and bioRxiv to search the studies, and the eligible criteria include (1) article written in English, (2) use of viral vectors expressing GAD67 or GAD65, and (3) preclinical pain models. We identified 13 eligible original research articles, in which the pain models include nerve injury, HIV-related pain, painful diabetic neuropathy, and formalin test. GAD expressed by the viral vectors from all the reports produced antinociceptive effects. Restoring GABA systems is a promising therapeutic strategy for chronic pain, which provides evidence for the clinical trial of gene therapy for pain in the near future.
Topics: AIDS-Associated Nephropathy; Accessory Nerve Injuries; Animals; Chronic Pain; Diabetic Neuropathies; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glutamate Decarboxylase; Humans; Mice; Rats; Simplexvirus; Spinal Cord Injuries; gamma-Aminobutyric Acid
PubMed: 32041431
DOI: 10.1089/hum.2019.359 -
PloS One 2015Several studies have demonstrated that renal transplantation in HIV positive patients is both safe and effective. However, none of these studies have specifically...
INTRODUCTION
Several studies have demonstrated that renal transplantation in HIV positive patients is both safe and effective. However, none of these studies have specifically examined outcomes in patients with HIV-associated nephropathy (HIVAN).
METHODS
Medical records of all HIV-infected patients who underwent kidney transplantation at Johns Hopkins Hospital between September 2006 and January 2014 were reviewed. Data was collected to examine baseline characteristics and outcomes of transplant recipients with HIVAN defined pathologically as collapsing focal segmental glomerulosclerosis (FSGS) with tubulo-interstitial disease.
RESULTS AND DISCUSSION
During the study period, a total of 16 patients with HIV infection underwent renal transplantation. Of those, 11 patients were identified to have biopsy-proven HIVAN as the primary cause of their end stage renal disease (ESRD) and were included in this study. They were predominantly African American males with a mean age of 47.6 years. Seven (64%) patients developed delayed graft function (DGF), and 6 (54%) patients required post-operative dialysis within one week of transplant. Graft survival rates at 1 and 3 years were 100% and 81%, respectively. Acute rejection rates at 1 and 3 years were 18% and 27%, respectively. During a mean follow up of 3.4 years, one patient died.
CONCLUSIONS
Acute rejection rates in HIVAN patients in this study are higher than reported in the general ESRD population, which is similar to findings from prior studies of patients with HIV infection and ESRD of various causes. The high rejection rates appear to have no impact on short or intermediate term graft survival.
Topics: AIDS-Associated Nephropathy; Adult; Aged; Delayed Graft Function; Female; Graft Rejection; HIV-1; Humans; Kidney Transplantation; Male; Middle Aged
PubMed: 26061701
DOI: 10.1371/journal.pone.0129702 -
Kidney International Dec 2018Mounting evidence suggests that epigenetic modification is important in kidney disease pathogenesis. To determine whether epigenetic regulation is involved in...
Mounting evidence suggests that epigenetic modification is important in kidney disease pathogenesis. To determine whether epigenetic regulation is involved in HIV-induced kidney injury, we performed genome-wide methylation profiling and transcriptomic profiling of human primary podocytes infected with HIV-1. Comparison of DNA methylation and RNA sequencing profiles identified several genes that were hypomethylated with corresponding upregulated RNA expression in HIV-infected podocytes. Notably, we found only one hypermethylated gene with corresponding downregulated RNA expression, namely regulator of calcineurin 1 (RCAN1). Further, we found that RCAN1 RNA expression was suppressed in glomeruli in human diabetic nephropathy, IgA nephropathy, and lupus nephritis, and in mouse models of HIV-associated nephropathy and diabetic nephropathy. We confirmed that HIV infection or high glucose conditions suppressed RCAN1 expression in cultured podocytes. This suppression was alleviated upon pretreatment with DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine, suggesting that RCAN1 expression is epigenetically suppressed in the context of HIV infection and diabetic conditions. Mechanistically, increased expression of RCAN1 decreased HIV- or high glucose-induced nuclear factor of activated T cells (NFAT) transcriptional activity. Increased RCAN1 expression also stabilized actin cytoskeleton organization, consistent with the inhibition of the calcineurin pathway. In vivo, knockout of RCAN1 aggravated albuminuria and podocyte injury in mice with Adriamycin-induced nephropathy. Our findings suggest that epigenetic suppression of RCAN1 aggravates podocyte injury in the setting of HIV infection and diabetic nephropathy.
Topics: AIDS-Associated Nephropathy; Animals; Biopsy; Calcium-Binding Proteins; Cells, Cultured; DNA Methylation; DNA Modification Methylases; DNA-Binding Proteins; Datasets as Topic; Decitabine; Diabetic Nephropathies; Disease Models, Animal; Epigenesis, Genetic; Gene Knockout Techniques; Genome, Human; Glucose; HIV-1; Humans; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Mice; Mice, Knockout; Muscle Proteins; NFATC Transcription Factors; Podocytes; Primary Cell Culture; Up-Regulation
PubMed: 30366682
DOI: 10.1016/j.kint.2018.07.023 -
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