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1.
Int J Mol Sci ; 20(23)2019 Dec 03.
Article in English | MEDLINE | ID: mdl-31817054

ABSTRACT

OBJECTIVE: Trefoil factor family peptide 3 (TFF3) has been shown to support catabolic functions in cases of osteoarthritis (OA). As in joint physiology and diseases such as OA, the synovial membrane (SM) of the joint capsule also plays a central role. We analyze the ability of SM to produce TFF compare healthy SM and its secretion product synovial fluid (SF) with SM and SF from patients suffering from OA or rheumatoid arthritis (RA). METHODS: Real-time PCR and ELISA were used to measure the expression of TFFs in healthy SM and SM from patients suffering from OA or RA. For tissue localization, we investigated TFF1-3 in differently aged human SM of healthy donors by means of immunohistochemistry, real-time PCR and Western blot. RESULTS: Only TFF3 but not TFF1 and -2 was expressed in SM from healthy donors as well as cases of OA or RA on protein and mRNA level. In contrast, all three TFFs were detected in all samples of SF on the protein level. No significant changes were observed for TFF1 at all. TFF2 was significantly upregulated in RA samples in comparison to OA samples. TFF3 protein was significantly downregulated in OA samples in comparison to healthy samples and cases of RA significantly upregulated compared to OA. In contrast, in SM TFF3 protein was not significantly regulated. CONCLUSION: The data demonstrate the production of TFF3 in SM. Unexpectedly, SF contains all three known TFF peptides. As neither articular cartilage nor SM produce TFF1 and TFF2, we speculate that these originate with high probability from blood serum.


Subject(s)
Arthritis, Rheumatoid/metabolism , Osteoarthritis/metabolism , Synovial Fluid/metabolism , Synovial Membrane/metabolism , Trefoil Factor-1/metabolism , Trefoil Factor-2/metabolism , Trefoil Factor-3/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Peptides/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tissue Donors , Trefoil Factor-1/genetics , Trefoil Factor-2/genetics , Trefoil Factor-3/genetics
2.
Int J Mol Sci ; 20(17)2019 Sep 01.
Article in English | MEDLINE | ID: mdl-31480518

ABSTRACT

The aim of the study was to explore the possible role of Trefoil Factor Family peptide 3 (TFF3) for skeletal repair. The expression of TFF3 was analyzed in human joint tissues as well as in a murine bone fracture model. Serum levels of TFF3 following a defined skeletal trauma in humans were determined by ELISA. The mRNA expression of TFF3 was analyzed under normoxia and hypoxia. Expression analysis after stimulation of human mesenchymal progenitor cells (MPCs) with TFF3 was performed by RT2 Profiler PCR Array. The effect of recombinant human (rh)TFF3 on MPCs was analysed by different migration and chemotaxis assays. The effect on cell motility was also visualized by fluorescence staining of F-Actin. TFF3 was absent in human articular cartilage, but strongly expressed in the subchondral bone and periosteum of adult joints. Strong TFF3 immunoreactivity was also detected in murine fracture callus. Serum levels of TFF3 were significantly increased after skeletal trauma in humans. Expression analysis demonstrated that rhTFF3 significantly decreased mRNA of ROCK1. Wound healing assays showed increased cell migration of MPCs by rhTFF3. The F-Actin cytoskeleton was markedly influenced by rhTFF3. Cell proliferation was not increased by rhTFF3. The data demonstrate elevated expression of TFF3 after skeletal trauma. The stimulatory effects on cell motility and migration of MPCs suggest a role of TFF3 in skeletal repair.


Subject(s)
Actin Cytoskeleton/metabolism , Bone and Bones/physiology , Cell Movement , Trefoil Factor-3/metabolism , Aged , Aged, 80 and over , Animals , Bone and Bones/metabolism , Female , Fracture Healing , Gene Expression Regulation , Humans , Hypoxia , Mice , Mice, Inbred C57BL , Middle Aged , Trefoil Factor-3/physiology , rho-Associated Kinases/genetics
3.
Genet Med ; 20(6): 630-638, 2018 06.
Article in English | MEDLINE | ID: mdl-29758562

ABSTRACT

PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.


Subject(s)
Body Height/genetics , Female , Genetic Testing , Heterozygote , High-Throughput Nucleotide Sequencing , Humans , Male , Mutation , Pedigree , Phenotype , Sequence Analysis, DNA/methods , Exome Sequencing/methods
4.
Sci Rep ; 5: 11649, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-26130459

ABSTRACT

Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.


Subject(s)
Cytoplasmic Dyneins/genetics , Mutation/genetics , Cilia/metabolism , Codon, Nonsense/genetics , Cytoplasmic Dyneins/chemistry , Exome/genetics , Fibroblasts/metabolism , Fluorescent Antibody Technique , Heterozygote , Humans , Protein Structure, Tertiary , Sequence Analysis, DNA
5.
Arthritis Rheum ; 65(9): 2310-22, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23784913

ABSTRACT

OBJECTIVE: Wnt signaling plays a pivotal role in skeletal development and in the control of cartilage and bone turnover. We have recently shown that the secreted Wnt antagonist Wnt inhibitory factor 1 (WIF-1) is mainly expressed in the upper layers of epiphyseal and articular cartilage and, to a lesser extent, in bone. Nevertheless, WIF-1(-/-) mice develop normally. In light of these findings, we undertook this study to analyze the role of WIF-1 in arthritis. METHODS: Expression analyses for WIF-1 were performed by real-time reverse transcription-polymerase chain reaction (RT-PCR). WIF-1(-/-) and tumor necrosis factor (TNF)-transgenic mice were crossbred, and the progression of arthritis in TNF-transgenic WIF-1(-/-) mice and littermate controls was evaluated. Structural joint damage was analyzed by histologic staining, histomorphometry, and micro-computed tomography. Wnt/ß-catenin signaling was investigated by real-time RT-PCR and immunofluorescence on primary chondrocytes. RESULTS: WIF-1 expression was repressed by TNFα in chondrocytes and osteoblasts and down-regulated in experimental arthritis and in articular cartilage from patients with rheumatoid arthritis. WIF-1 deficiency partially protected TNF-transgenic mice against bone erosion and loss of trabecular bone, probably as a result of less osteoclast activity. In contrast, arthritis-related cartilage damage was aggravated by WIF-1 deficiency, while overexpression of WIF-1 attenuated cartilage degradation in TNF-transgenic mice. In chondrocytes, TNFα stimulated canonical Wnt signaling, which could be blocked by WIF-1, indicating a direct effect of TNFα and WIF-1 on Wnt signaling in this system. CONCLUSION: These data suggest that WIF-1 may take part in the fine-tuning of cartilage and bone turnover, promoting the balance of cartilage versus bone anabolism.


Subject(s)
Arthritis, Experimental/metabolism , Bone and Bones/metabolism , Cartilage/metabolism , Extracellular Matrix Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Tumor Necrosis Factor-alpha/metabolism , Adaptor Proteins, Signal Transducing , Animals , Arthritis, Experimental/genetics , Arthritis, Experimental/pathology , Bone and Bones/pathology , Cartilage/pathology , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Chondrocytes/metabolism , Chondrocytes/pathology , Disease Progression , Down-Regulation , Extracellular Matrix Proteins/genetics , Humans , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Knockout , Mice, Transgenic , Tumor Necrosis Factor-alpha/genetics
6.
J Clin Invest ; 123(4): 1428-43, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23549083

ABSTRACT

Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.


Subject(s)
Colitis/complications , Colorectal Neoplasms/etiology , Epidermal Growth Factor/physiology , Fibroblasts/metabolism , MAP Kinase Signaling System , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colitis/chemically induced , Colon/pathology , Colorectal Neoplasms/pathology , Epidermal Growth Factor/genetics , Epidermal Growth Factor/metabolism , Epiregulin , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibroblasts/pathology , Fibroblasts/transplantation , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Ki-67 Antigen/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Transcriptome , Tumor Burden
7.
Cartilage ; 4(3): 249-55, 2013 Jul.
Article in English | MEDLINE | ID: mdl-26069671

ABSTRACT

OBJECTIVE: To identify factors that are responsible for the phenotypic differences between transient chondrocytes within human osteophytes prone to endochondral ossification and permanent chondrocytes within articular cartilage persisting for decades. METHODS: Differential gene expression of chondrocytes from human osteophytes or from articular cartilage was detected by cDNA microarray analysis. The expression of pigment epithelium-derived factor (PEDF), one of the most impressively differentially expressed genes, was validated by quantitative reverse transcriptase polymerase chain reaction as well as immunohistochemistry. The mode of action of PEDF was explored by cell viability assays and by detecting target genes. RESULTS: PEDF mRNA expression was upregulated by 118.5-fold (P = 0.01) in human osteophytic cartilage compared with articular cartilage, which was reflected by strong immunostaining for PEDF in the cartilaginous layer of osteophytes but largely negative staining in articular cartilage. Elevated levels of PEDF in osteophytes were associated with enhanced apoptosis. PEDF increased the expression of the proapoptotic factor FasL and induced cell death in cell culture. Osteochondral progenitor cells were more responsive to PEDF than differentiated articular chondrocytes. CONCLUSIONS: The induction of the proapoptotic factor PEDF within the osteophyte cartilage suggests a molecular concept for the transient chondrocyte phenotype that arises from progenitor cells and is prone to terminal differentiation and cell death.

8.
Tissue Eng Part A ; 17(15-16): 2101-12, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21513464

ABSTRACT

This study investigated the effect of thrombospondin-1 (TSP-1) on the formation of cartilage repair tissue in combination with stimulation by osteogenic protein-1 (OP-1). In miniature pigs, articular cartilage lesions in the femoral trochlea were treated by the microfracture technique and either received no further treatment (MFX), or were treated by additional application of recombinant osteogenic protein-1 (MFX+OP-1), recombinant TSP-1 (MFX+TSP-1), or a combination of both proteins (MFX+TSP-1+OP-1). Six and 26 weeks after surgery, the repair tissue and the degree of endochondral ossification were assessed by histochemical and immunohistochemical methods detecting collagen types I, II, X, TSP-1, and CD31. Microfracture treatment merely induced the formation of inferior fibrocartilaginous repair tissue. OP-1 stimulated chondrogenesis, but also induced chondrocyte hypertrophy, characterized by synthesis of collagen type X, and excessive bone formation. Application of TSP-1 inhibited inadvertant endochondral ossification, but failed to induce chondrogenesis. In contrast, the simultaneous application of both TSP-1 and OP-1 induced and maintained a permanent, nonhypertrophic chondrocyte-like phenotype within cartilage repair tissue. The data of this study demonstrate that OP-1 and TSP-1 complement each other in a functional manner. While OP-1 induces chondrogenesis of the ingrowing cells, TSP-1 prevents their further hypertrophic differentiation and prevents excessive endochondral ossification within the lesions.


Subject(s)
Bone Morphogenetic Protein 7/pharmacology , Chondrogenesis , Osteogenesis/drug effects , Thrombospondin 1/pharmacology , Wound Healing/drug effects , Animals , Arthroplasty, Subchondral , Blood Vessels/drug effects , Blood Vessels/pathology , Cartilage Diseases/drug therapy , Cartilage Diseases/pathology , Cartilage Diseases/physiopathology , Cartilage Diseases/surgery , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cartilage, Articular/surgery , Cell Differentiation/drug effects , Chondrocytes/drug effects , Chondrocytes/pathology , Chondrogenesis/drug effects , Combined Modality Therapy , Endothelial Cells/drug effects , Female , Humans , Hypertrophy , Neovascularization, Physiologic/drug effects , Stress, Mechanical , Swine , Swine, Miniature
9.
Arthritis Rheum ; 63(9): 2721-31, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21391200

ABSTRACT

OBJECTIVE: To investigate the effect of chondromodulin 1 on the phenotype of osteochondral progenitor cells in cartilage repair tissue. METHODS: Self-complementary adeno-associated virus (AAV) vectors carrying chondromodulin 1 complementary DNA (AAV-Chm-1) were applied to cartilage lesions in the knee joints of miniature pigs that were treated by the microfracture technique. Alternatively, isolated porcine osteochondral progenitor cells were infected with AAV-Chm-1 or with AAV-GFP control vectors ex vivo prior to being transplanted into cartilage lesions in which the subchondral bone plate was left intact. The quality of the repair tissue and the degree of endochondral ossification were assessed by histochemical and immunohistochemical methods. The effects of chondromodulin 1 overexpression were also analyzed by angiogenesis assays and quantitative reverse transcriptase-polymerase chain reaction. RESULTS: AAV-Chm-1-infected cells efficiently produced chondromodulin 1, which had strong antiangiogenic effects, as verified by the inhibition of tube formation of endothelial cells. Gene expression analyses in vitro revealed the cell cycle inhibitor p21WAF1/Cip1 as one target up-regulated by AAV-Chm-1. Direct application of AAV-Chm-1 vectors into microfractured porcine cartilage lesions stimulated chondrogenic differentiation of ingrowing progenitor cells, but significantly inhibited terminal chondrocyte hypertrophy, the invasion of vessel structures, and excessive endochondral ossification, which were otherwise observed in untreated lesions. Indirect gene transfer, with infection of porcine osteochondral progenitor cells by AAV-Chm-1 ex vivo, also supported chondrogenic differentiation of these transplanted cells. AAV-Chm-1-infected cells maintained a chondrocyte-like phenotype and formed a hyaline-like matrix that was superior to that formed by uninfected or AAV-GFP-infected cells. CONCLUSION: Our findings indicate that the antiangiogenic factor chondromodulin 1 stabilizes the chondrocyte phenotype by supporting chondrogenesis but inhibiting chondrocyte hypertrophy and endochondral ossification.


Subject(s)
Cartilage/metabolism , Chondrocytes/metabolism , Chondrogenesis/physiology , Intercellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Osteogenesis/physiology , Wound Healing/physiology , Animals , Cell Survival/physiology , Gene Expression , Humans , Stem Cells , Swine
10.
Transcription ; 2(6): 269-75, 2011.
Article in English | MEDLINE | ID: mdl-22223045

ABSTRACT

Hypoxia-inducible factors (HIF1α/HIF2α) are key transcription factors that promote angiogenesis. The overexpression of degradation-resistant HIF mutants is considered a promising pro-angiogenic therapeutic tool. We compared the transcriptional activity of HIF1α/HIF2α mutants that obtained their resistance to oxygen-dependent degradation either by deletion of their entire oxygen-dependent degradation (ODD) domain or by replacement of prolyl residues that are crucial for oxygen-dependent degradation. Although all HIF mutants translocated into the nucleus, HIF1α and HIF2α mutants inclosing the point mutations were significantly more effective in trans-activating the target gene VEGF and in inducing tube formation of endothelial cells than mutants lacking the complete ODD domain.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Gene Deletion , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Point Mutation , Transcription, Genetic/genetics , Active Transport, Cell Nucleus , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Binding Sites/genetics , Cell Line , Cell Nucleus/metabolism , Endothelial Cells/metabolism , Endothelial Cells/physiology , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Immunoblotting , Luciferases/genetics , Luciferases/metabolism , Mice , Microscopy, Fluorescence , Neovascularization, Physiologic , Oxygen/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcriptional Activation , Transfection , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
11.
J Orthop Res ; 27(9): 1216-25, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19274742

ABSTRACT

The study's objective was to investigate if transplanted chondrocyte or periosteal cell spheroids have influence on ingrowing bone marrow-derived cells in a novel cartilage repair approach in miniature pigs. Autologous rib chondrocytes or periosteal cells were cultured as spheroids and press-fitted into cavities that were milled into large, superficial chondral lesions of the patellar joint surface. Within the milled cavities, the subchondral bone plate was either penetrated or left intact (full-thickness or partial-thickness cavities). The transplantation of chondrocyte spheroids into full-thickness cavities induced the formation of additional secondary repair cartilage that exceeded the original volume of the transplanted spheroids. The resulting continuous tissue was rich in proteoglycans and stained positive for type II collagen. Cell labeling revealed that secondarily invading repair cells did not originate from transplanted spheroids, but rather from arroded bone marrow. However, secondary invasion of repair cells was less pronounced following transplantation of periosteal cells and absent in partial-thickness cavities. According to in vitro analyses, these observations could be ascribed to the ability of chondrocyte spheroids to secrete relevant amounts of bone morphogenetic protein-2, which was not detected for periosteal cells. Transplanted chondrocyte spheroids exert a dual function: they provide cells for the repair tissue and have a stimulatory paracrine activity, which promotes ingrowth and chondrogenesis of bone marrow-derived cells.


Subject(s)
Cartilage/injuries , Chondrocytes/metabolism , Chondrocytes/transplantation , Chondrogenesis/physiology , Paracrine Communication/physiology , Ribs/cytology , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Bone Morphogenetic Protein 2/metabolism , Cartilage/cytology , Cartilage/metabolism , Cells, Cultured , Chondrocytes/cytology , Collagen Type II/metabolism , Female , Humans , Proteoglycans/metabolism , Spheroids, Cellular/cytology , Spheroids, Cellular/metabolism , Spheroids, Cellular/transplantation , Stem Cells/cytology , Stem Cells/metabolism , Swine , Swine, Miniature , Wound Healing/physiology
12.
J Biol Chem ; 280(52): 42515-27, 2005 Dec 30.
Article in English | MEDLINE | ID: mdl-16234236

ABSTRACT

The human immunodeficiency virus type 1 p6 protein represents a docking site for several cellular and viral binding factors and fulfills major roles in the formation of infectious viruses. To date, however, the structure of this 52-amino acid protein, by far the smallest lentiviral protein known, either in its mature form as free p6 or as the C-terminal part of the Pr55 Gag polyprotein has not been unraveled. We have explored the high resolution structure and folding of p6 by CD and NMR spectroscopy. Under membranous solution conditions, p6 can adopt a helix-flexible helix structure; a short helix-1 (amino acids 14-18) is connected to a pronounced helix-2 (amino acids 33-44) by a flexible hinge region. Thus, p6 can be subdivided into two distinct structural and functional domains; helix-2 perfectly defines the region that binds to the virus budding factor AIP-1/ALIX, indicating that this structure is required for interaction with the endosomal sorting complex required for transport. The PTAP motif at the N terminus, comprising the primary late assembly domain, which is crucial for interaction with another cellular budding factor, Tsg101, does not exhibit secondary structure. However, the adjacent helix-1 may play an indirect role in the specific complex formation between p6 and the binding groove in Tsg101. Moreover, binding studies by NMR demonstrate that helix-2, which also comprises the LXXLF motif required for incorporation of the human immunodeficiency virus type 1 accessory protein Vpr into budding virions, specifically interacts with the Vpr binding region, indicating that under the specific solution conditions used for structure analysis, p6 adopted a functional conformation.


Subject(s)
Gene Products, gag/chemistry , Amino Acid Motifs , Amino Acid Sequence , Blotting, Western , CD4-Positive T-Lymphocytes/virology , Circular Dichroism , DNA-Binding Proteins/chemistry , Electrophoresis, Polyacrylamide Gel , Endosomal Sorting Complexes Required for Transport , Gene Products, gag/metabolism , Gene Products, vpr/chemistry , Humans , Immunoprecipitation , Magnetic Resonance Spectroscopy , Models, Molecular , Peptides/chemistry , Protein Binding , Protein Conformation , Protein Structure, Secondary , Protein Structure, Tertiary , Protons , Transcription Factors/chemistry , gag Gene Products, Human Immunodeficiency Virus
13.
Expert Rev Anti Infect Ther ; 3(1): 61-79, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15757458

ABSTRACT

Since the discovery of HIV approximately 20 years ago, more than 60 million individuals have been infected, and AIDS still remains one of the most devastating diseases humankind has ever faced. Unfortunately, there is little hope that an effective vaccine will be developed in the near future. Current antiretroviral treatment is based on drugs that either target the viral enzymes (protease and reverse transcriptase) or the attachment and entry of the virus. Although the introduction of highly active antiretroviral therapy in the mid-1990s has led to a profound reduction in HIV-related morbidity and mortality, the complete eradication of the virus from infected individuals has never been achieved. In addition, these antiviral drugs can induce serious adverse effects, particularly when administered in combination over prolonged treatment periods. A further drawback to these treatments is that with the high mutation rate of HIV, drug-resistant mutants are evolving, particularly when antiretroviral treatment only suppresses virus replication to marginal levels in latently infected cells making up the virus reservoirs in vivo. Cellular genes have much lower mutation rates, and drug-mediated modulation of specific cellular pathways represents an attractive antiviral strategy. Recent findings showing that proteasome inhibitors interfere with budding, maturation and infectivity of HIV have triggered intensive investigation of the hitherto unappreciated function of the ubiquitin-proteasome system in HIV replication. It was also observed that, like several other retroviruses, HIV-1 virions contain a small amount of mono-ubiquitinylated Gag proteins. Currently, two E3-type ubiquitin ligases, in addition to one E3-like protein, have been identified as regulators of HIV budding. These ligases might represent interesting targets for therapeutic intervention.


Subject(s)
Anti-Retroviral Agents/administration & dosage , Drug Delivery Systems/methods , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , Animals , Anti-Retroviral Agents/metabolism , HIV-1/drug effects , HIV-1/genetics , HIV-1/metabolism , Humans , Proteasome Endopeptidase Complex/genetics , Proteasome Inhibitors , Ubiquitin/antagonists & inhibitors , Ubiquitin/genetics
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