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Journal of Clinical Virology : the... Apr 2016HHV7 reactivation has been occasionally reported as a cause of encephalitis or myelitis in transplant recipients, but to our knowledge it has never been associated with... (Review)
Review
BACKGROUND
HHV7 reactivation has been occasionally reported as a cause of encephalitis or myelitis in transplant recipients, but to our knowledge it has never been associated with neurological disease in HIV-infected patients. We report a case of acute myelitis in an HIV-infected patient, with sustained HHV-7 DNA amplification in cerebrospinal fluid (CSF) and a favourable response to foscarnet.
CASE REPORT
A 40 year-old man with HIV infection was admitted with asymmetric hypoesthesia in legs and paraparesis. He was receiving treatment with efavirenz, emtricitabine and tenofovir, his CD4 count was 580/mm3 and HIV viral load was undetectable. Magnetic resonance imaging showed a focal central hyperintensity on T2 and STIR sequences, on the torathic spinal cord, with slight enhancement after intravenous gadolinium. All microbiological studies were negative except for HHV-7 DNA amplification in CSF. With a diagnosis of idiopathic transverse myelitis, treatment with high-dose intravenous methylprednisolone was initiated. However, paraparesis continued worsening, and a second CSF obtained 12 days after the first one resulted again in HHV-7 amplification.
RESULTS
The patient was treated with a 2 week course of foscarnet, and a rapid neurological improvement was noted. After treatment, PCR for HHV-7 in CSF was negative. Neurological exam was normal one month after treatment initiation.
CONCLUSION
HHV-7 reactivation may cause neurological disease in patients with HIV infection. Foscarnet is an effective treatment in HHV-7 associated myelitis.
Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Coinfection; DNA, Viral; Foscarnet; HIV Infections; Herpesvirus 7, Human; Humans; Magnetic Resonance Imaging; Male; Myelitis; Roseolovirus Infections; Spinal Cord; Treatment Outcome; Viral Load; Virus Activation
PubMed: 26906233
DOI: 10.1016/j.jcv.2016.02.001 -
Accounts of Chemical Research Oct 2020Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of...
Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of therapeutic oligonucleotides are single-stranded antisense oligonucleotides (ASOs), double stranded small interfering RNAs (siRNAs), and oligonucleotides that induce exon skipping. Recently, ASOs, siRNAs, and exon skipping oligonucleotides have been approved for patients with unmet medical needs, and many other candidates are being tested in late stage clinical trials. In coming years, therapeutic oligonucleotides may match the promise of small molecules and antibodies. Interestingly, in the 1980s when we developed chemical methods for synthesizing oligonucleotides, no one would have imagined that these highly charged macromolecules could become future medicines. Indeed, the anionic nature and poor metabolic stability of the natural phosphodiester backbone provided a major challenge for the use of oligonucleotides as therapeutic drugs. Thus, chemical modifications of oligonucleotides were essential in order to improve their pharmacokinetic properties. Keeping this view in mind, my laboratory has developed a series of novel oligonucleotides where one or both nonbridging oxygens in the phosphodiester backbone are replaced with an atom or molecule that introduces molecular properties that enhance biological activity. We followed two complementary approaches. One was the use of phosphoramidites that could act directly as synthons for the solid phase synthesis of oligonucleotide analogues. This approach sometimes was not feasible due to instability of various synthons toward the reagents used during synthesis of oligonucleotides. Therefore, using a complementary approach, we developed phosphoramidite synthons that can be incorporated into oligonucleotides with minimum changes in the solid phase DNA synthesis protocols but contain a handle for generating appropriate analogues postsynthetically.This Account summarizes our efforts toward preparing these types of analogues over the past three decades and discusses synthesis and properties of backbone modified oligonucleotides that originated from the Caruthers' laboratory. For example, by replacing one of the internucleotide oxygens with an acetate group, we obtained so-called phosphonoacetate oligonucleotides that were stable to nucleases and, when delivered as esters, entered into cells unaided. Alternatively oligonucleotides bearing borane phosphonate linkages were found to be RNase H active and compatible with the endogenous RNA induced silencing complex (RISC). Oligonucleotides containing an alkyne group directly linked to phosphorus in the backbone were prepared as well and used to attach molecules such as amino acids and peptides.
Topics: Boranes; DNA; Foscarnet; Oligonucleotides; Organophosphonates; Organophosphorus Compounds; Phosphines; Phosphonoacetic Acid; Phosphorus
PubMed: 32885957
DOI: 10.1021/acs.accounts.0c00078 -
Cutis Jan 2017
Topics: Antiviral Agents; Female; Foscarnet; Humans; Ulcer; Vulvar Diseases; Young Adult
PubMed: 28207008
DOI: No ID Found -
Journal of Renal Nutrition : the... Mar 2022Vascular calcification (VC) is an important risk factor for cardiovascular disease in maintenance hemodialysis (MHD) patients. Hyperphosphatemia and microinflammation...
OBJECTIVE
Vascular calcification (VC) is an important risk factor for cardiovascular disease in maintenance hemodialysis (MHD) patients. Hyperphosphatemia and microinflammation statement are known major contributors to the development of VC; however, the mechanisms are unknown. The aims of this study were to explore the risk factors of VC in MHD patients and to explore whether high phosphate could increase the secretion of inflammatory cytokines via PiT-1 in monocytes.
METHODS
A cross-sectional study was conducted on 65 MHD patients to assess the relevance of coronary artery calcification (CAC), inflammatory factors, serum phosphate, and sodium-dependent phosphate cotransporter (NPT) mRNA expression of peripheral blood mononuclear cells (PBMCs). Multivariate logistic regression analysis was used to analyze the predictors of CAC. The calcification effects of high phosphate (HP), TNF-α, and supernatants of healthy human monocytes treated with HP were further evaluated in cultured HASMCs.
RESULTS
Diabetes, longer dialysis vintage, higher serum TNF-α levels, and PiT-1 mRNA expression of PBMCs) were independent risk factors of CAC in MHD patients. The mRNA levels of PiT-1 in PBMCs were positively correlated with serum phosphate, CAC scores, and Pit-2 mRNA levels of PBMCs. The expressions of TNF-α, IL-6, and PiT-1 in human monocytes were significantly increased in a dose-dependent manner after treatment with HP, which was subsequently inhibited by NPT antagonist phosphonoformic acid. Neither TNF-α alone nor supernatants of monocytes stimulated with HP promoted the expression of osteopontin and Runt-related transcription factor 2 (Runx2) or caused mineralization in human aortic smooth muscle cells, but combined with HP intervention, the calcification effects were markedly increased in human aortic smooth muscle cells and ameliorated by phosphonoformic acid treatment.
CONCLUSION
Hyperphosphatemia directly increased the synthesis and secretion of TNF-α by monocytes may via PiT-1 pathway, resulting in elevated systemic inflammatory response, which may further aggravate VC induced by phosphate overload in MHD patients.
Topics: Cells, Cultured; Cross-Sectional Studies; Female; Foscarnet; Humans; Hyperphosphatemia; Leukocytes, Mononuclear; Male; Muscle, Smooth, Vascular; Phosphates; RNA, Messenger; Sodium-Phosphate Cotransporter Proteins, Type III; Tumor Necrosis Factor-alpha; Uremia; Vascular Calcification
PubMed: 34688540
DOI: 10.1053/j.jrn.2021.03.008 -
The Journal of Infectious Diseases Feb 2018Genital herpes is an important cofactor for acquisition of human immunodeficiency virus (HIV) infection, and effective prophylaxis is a helpful strategy to halt both HIV...
BACKGROUND
Genital herpes is an important cofactor for acquisition of human immunodeficiency virus (HIV) infection, and effective prophylaxis is a helpful strategy to halt both HIV and herpes simplex virus (HSV) transmission. The antiretroviral agent tenofovir, formulated as a vaginal microbicide gel, was shown to reduce the risk of HIV and HSV type 2 (HSV-2) acquisition.
METHODS
HSV type 1 (HSV-1) and HSV-2 mutants were selected for resistance to tenofovir and PMEO-DAPy (6-phosphonylmethoxyethoxy-2,4-diaminopyrimidine, an acyclic nucleoside phosphonate with dual anti-HSV and anti-HIV activity) by stepwise dose escalation. Several plaque-purified viruses were characterized phenotypically (drug resistance profiling) and genotypically (sequencing of the viral DNA polymerase gene).
RESULTS
Tenofovir resistant and PMEO-DAPy-resistant viruses harbored specific amino acid substitutions associated with resistance not only to tenofovir and PMEO-DAPy but also to acyclovir and foscarnet. These amino acid changes (A719V, S724N, and L802F [HSV-1] and M789T and A724V [HSV-2]) were also found in clinical isolates recovered from patients refractory to acyclovir and/or foscarnet therapy or in laboratory-derived strains. A total of 10 (HSV-1) and 18 (HSV-2) well-characterized DNA polymerase mutants had decreased susceptibility to tenofovir and PMEO-DAPy.
CONCLUSIONS
Tenofovir and PMEO-DAPy target the HSV DNA polymerase, and clinical isolates with DNA polymerase mutations emerging under acyclovir and/or foscarnet therapy showed cross-resistance to tenofovir and PMEO-DAPy.
Topics: Acyclovir; Amino Acid Substitution; Antiviral Agents; Cells, Cultured; DNA Mutational Analysis; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Exodeoxyribonucleases; Foscarnet; Herpes Genitalis; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Mutation, Missense; Organophosphonates; Pyrimidines; Reverse Transcriptase Inhibitors; Selection, Genetic; Sequence Analysis, DNA; Tenofovir; Viral Proteins
PubMed: 29186456
DOI: 10.1093/infdis/jix605 -
Nanoscale Sep 2019Magnetic nanoparticles (MNPs) internalized within stem cells have paved the way for remote magnetic cell manipulation and imaging in regenerative medicine. A full...
Magnetic nanoparticles (MNPs) internalized within stem cells have paved the way for remote magnetic cell manipulation and imaging in regenerative medicine. A full understanding of their interactions with stem cells and of their fate in the intracellular environment is then required, in particular with respect to their surface coatings. Here, we investigated the biological interactions of MNPs composed of an identical magnetic core but coated with different molecules: phosphonoacetic acid, polyethylene glycol phosphonic carboxylic acid, caffeic acid, citric acid, and polyacrylic acid. These coatings vary in the nature of the chelating function, the number of binding sites, and the presence or absence of a polymer. The nanoparticle magnetism was systematically used as an indicator of their internalization within human stem cells and of their structural long-term biodegradation in a 3D stem cell spheroid model. Overall, we evidence that the coating impacts the aggregation status of the nanoparticles and subsequently their uptake within stem cells, but it has little effect on their intracellular degradation. Only a high number of chelating functions (polyacrylic acid) had a significant protective effect. Interestingly, when the nanoparticles aggregated prior to cellular internalization, less degradation was also observed. Finally, for all coatings, a robust dose-dependent intracellular degradation rate was demonstrated, with higher doses of internalized nanoparticles leading to a lower degradation extent.
Topics: Coated Materials, Biocompatible; Humans; Magnetite Nanoparticles; Mesenchymal Stem Cells; Spheroids, Cellular
PubMed: 31453605
DOI: 10.1039/c9nr05624f -
Molecules (Basel, Switzerland) Sep 2022The chemical reactivity of 3-[()-3-(dimethylamino)-2-propenoyl]-4-hydroxy-1-methy-2(1)-quinolinone () towards some phosphorus reagents was studied. The enaminone was...
The chemical reactivity of 3-[()-3-(dimethylamino)-2-propenoyl]-4-hydroxy-1-methy-2(1)-quinolinone () towards some phosphorus reagents was studied. The enaminone was cyclized into pyranoquinolinylphosphonate via treatment with diethyl phosphite in basic medium. However, its reaction with triethoxy phosphonoacetate gave the substituted oxopyranylphosphonate . Using the same reaction conditions, both thioxopyridinylphosphonate and oxopyranylphosphonate were produced via a reaction of enaminone with both diethyl 2-amino-2-thioxoethylphosphonate and diethyl vinylphosphonate, respectively, in low yields. In addition, the two novel oxopyridinylphosphonates and were obtained by treatment of enaminone with a diethyl cyanomethylphosphonate reagent. Two oaxathiaphosphininyl derivatives, and were obtained by treatment of the enaminone with -diethyl dithiophosphoric acid under different reaction conditions. Diazaphosphininyl and oxazaphosphininyl derivatives were obtained in excellent yields using a -phenylphosphonic diamide reagent under different reaction conditions. The treatment of the enaminone with phosphorus pentasulfide produced the non-phosphorylated product thioxothiopyranoquinolinone . Finally, the enaminone was turned into oxathiaphosphininyl using Lawesson's reagent. The possible reaction mechanisms of the formation of these products were discussed. The structures of newly isolated products were established by elemental analysis and spectral tools. The compounds were evaluated for their antioxidant activities.
Topics: Antioxidants; Diamide; Indicators and Reagents; Organophosphonates; Phosphites; Phosphonoacetic Acid; Phosphorus; Quinolones
PubMed: 36144697
DOI: 10.3390/molecules27185960 -
Journal of the Neurological Sciences May 2018Cytomegalovirus (CMV) is a ubiquitous herpesvirus which establishes lifelong latency following primary infection. It is then capable of reactivating in the face of... (Review)
Review
Cytomegalovirus (CMV) is a ubiquitous herpesvirus which establishes lifelong latency following primary infection. It is then capable of reactivating in the face of immunosuppression. Encephalitis is a less common, but particularly devastating syndrome associated with CMV. Here, we describe a case of CMV encephalitis in an allogeneic hematopoietic stem cell transplant recipient who received dual antiviral therapy with ganciclovir and foscarnet. The case presentation is followed by a summary of cases reported in the last ten years, with the goal of describing vulnerable patient populations, treatment courses, and outcomes. Finally, the discussion includes a review of the literature, with a focus on diagnostic criteria and the role for dual antiviral therapy in CMV encephalitis.
Topics: Antiviral Agents; Cytomegalovirus Infections; Drug Therapy, Combination; Encephalitis, Viral; Female; Foscarnet; Ganciclovir; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Middle Aged; Transplantation, Homologous
PubMed: 29627026
DOI: 10.1016/j.jns.2018.02.029 -
Antiviral Research Aug 2023Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis...
Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis by next-generation sequencing (NGS). Here, we report novel UL23 and UL30 substitutions for HSV1 and HSV2 identified in immunocompromised patients treated for hematological malignancies during the last 6 years of HSV resistance surveillance at the University Hospital of Lyon. For HSV1, 35 novel UL23 substitutions and 52 novel UL30 substitutions were identified. For HSV2, 2 novel UL23 substitutions and 12 novel UL30 substitutions were identified. These results allow to complete the database of HSV1 and HSV2 substitutions, related either to polymorphism or to ACV and FOS resistance.
Topics: Humans; Antiviral Agents; Herpes Simplex; Herpesvirus 1, Human; Viral Proteins; Drug Resistance, Viral; Acyclovir; Foscarnet
PubMed: 37453453
DOI: 10.1016/j.antiviral.2023.105672 -
Gut Jan 2020Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk...
OBJECTIVE
Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent.
DESIGN
Here, we combined an RNAi loss-of-function and small molecule screen to uncover host-dependency factors for HDV infection.
RESULTS
Functional screening unravelled the hypoxia-inducible factor (HIF)-signalling and insulin-resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus-hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl-phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by ) as key host factors for HDV life cycle. Mechanistic studies revealed that the two host factors are required for viral replication. Inhibition studies using N-(phosphonoacetyl)-L-aspartic acid and fulvestrant, specific CAD and ESR1 inhibitors, respectively, uncovered their impact as antiviral targets.
CONCLUSION
The discovery of HDV host-dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.
Topics: Antiviral Agents; Aspartate Carbamoyltransferase; Aspartic Acid; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); Cell Line; Dihydroorotase; Estrogen Receptor Antagonists; Estrogen Receptor alpha; Fulvestrant; Gene Silencing; Hepatitis D, Chronic; Hepatitis Delta Virus; Hepatocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin Resistance; Life Cycle Stages; Loss of Function Mutation; Phosphonoacetic Acid; Pyrimidines; RNA Interference; RNA, Small Interfering; RNA, Viral; Signal Transduction; Virus Replication
PubMed: 30833451
DOI: 10.1136/gutjnl-2018-317065