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Methylation & HIV

Stephanie Shiau, Renate Strehlau, Jing Shen, Avy Violari, Faeezah Patel, Afaaf Liberty, Marc Foca, Shuang Wang, Mary Beth Terry, Michael T Yin, Ashraf Coovadia, Elaine J Abrams, Stephen M Arpadi, Louise Kuhn
BACKGROUND: Data on accelerated aging in HIV-infected children are limited. In this study we assess two biomarkers of aging - telomere length and DNA methylation (DNAm) age - in a cohort of early-treated HIV-infected children and compare these aging biomarkers to HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children. SETTING: Cross-sectional study of 120 HIV-infected, 33 HEU, and 25 HUU children enrolled in a cohort study in Johannesburg, South Africa...
April 27, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Palsamy Periyasamy, Annadurai Thangaraj, Ming-Lei Guo, Guoku Hu, Shannon Callen, Shilpa Buch
The present study demonstrates HIV-1 Tat-mediated epigenetic downregulation of microglial miR-124 and its association with microglial activation. Exposure of mouse primary microglia isolated from newborn pups of either sex to HIV-1 Tat resulted in decreased expression of primary miR-124-1, primary miR-124-2 as well as the mature miR-124. In parallel, HIV-1 Tat exposure to mouse primary microglial cells resulted in increased expression of DNA methylation enzymes, such as DNMT1, DNMT3A, and DNMT3B that were also accompanied by increased global DNA methylation...
May 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Georges Khoury, Talia M Mota, Shuang Li, Carolin Tumpach, Michelle Y Lee, Jonathan Jacobson, Leigh Harty, Jenny L Anderson, Sharon R Lewin, Damian F J Purcell
BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing...
May 11, 2018: Retrovirology
Steve Horvath, Nicole Phillips, Sarah J Heany, Michael S Kobor, David Ts Lin, Landon Myer, Heather J Zar, Dan J Stein, Andrew J Levine, Jacqueline Hoare
OBJECTIVE: Recent studies demonstrate that infection with the Human Immunodeficiency Virus-1 (HIV) is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. However, it not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally HIV-infected (PHIV+) youth. DESIGN: Observational study of PHIV and HIV-uninfected adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) Study...
May 8, 2018: AIDS
Mohammad A Rahman, Yuqing Gong, Santosh Kumar
Diallyl sulfide (DAS) has been shown to prevent xenobiotic (e.g. ethanol, acetaminophen) induced toxicity and disease (e.g. HIV-1) pathogenesis. DAS imparts its beneficial effect by inhibiting CYP2E1-mediated metabolism of xenobiotics, especially at high concentration. However, DAS also causes toxicity at relatively high dosages and with long exposure times. Therefore, the goal of the current study was to investigate the structural analogs of DAS for their improved toxicity profiles and their effectiveness in reducing xenobiotic-induced toxicity and HIV-1 replication...
April 22, 2018: Toxicology Letters
Manish B Shah, Qinghai Zhang, James R Halpert
The over two dozen CYP2B structures of human, rabbit, and woodrat enzymes solved in the last decade have significantly enhanced our understanding of the structure-function relationships of drug metabolizing enzymes. More recently, an important role has emerged for halogen-π interactions in the CYP2B6 active site in substrate selectivity, explaining in part the preference for halogenated ligands as substrates. The mechanism by which such ligands interact with CYP2B enzymes involves conserved phenylalanine side chains, in particular F108, F115, or F297, in the active site, which form π bonds with halogens...
March 29, 2018: International Journal of Molecular Sciences
Katherine E Olson, Aditya N Bade, Krista L Namminga, Mary Jane Potash, R Lee Mosley, Larisa Y Poluektova, David J Volsky, Howard E Gendelman
The widespread use of antiretroviral therapy for treatment of human immunodeficiency virus (HIV) infections has dramatically improved the quality and duration of life for HIV-positive individuals. Despite this success, HIV persists for the life of an infected person in tissue reservoirs including the nervous system. Thus, whether HIV exacerbates age-related brain disorders such as Parkinson's disease (PD) is of concern. In support of this idea, HIV infection can be associated with motor and gait abnormalities that parallel late-stage manifestations of PD including dopaminergic neuronal loss...
March 28, 2018: Journal of Neurovirology
S A Amin, N Adhikari, S Bhargava, T Jha, S Gayen
The current study deals with chemometric modelling strategies (Naïve Bayes classification, hologram-based quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)) to explore the important features of hydroxylamine derivatives for exerting potent human immunodeficiency virus-1 (HIV-1) protease inhibition. Depending on the statistically validated reliable and robust quantitative structure-activity relationship (QSAR) models, important and crucial structural features have been identified that may be responsible for enhancing the activity profile of these hydroxylamine compounds...
March 23, 2018: SAR and QSAR in Environmental Research
Elaine Tseng, Gwendolyn D Fate, Gregory S Walker, Theunis C Goosen, R Scott Obach
Maraviroc (MVC) is a CCR5 coreceptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy. The sites of metabolism were the 2- and 3-positions of the 4,4-difluorocyclohexyl moiety and the methyl of the triazole moiety...
May 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Guochun Jiang, Don Nguyen, Nancie M Archin, Steven A Yukl, Gema Méndez-Lagares, Yuyang Tang, Maher M Elsheikh, George R Thompson, Dennis J Hartigan-O'Connor, David M Margolis, Joseph K Wong, Satya Dandekar
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2)...
March 1, 2018: Journal of Clinical Investigation
Roberta Nicoleta Bogoi, Alicia de Pablo, Eulalia Valencia, Luz Martín-Carbonero, Victoria Moreno, Helem Haydee Vilchez-Rueda, Victor Asensi, Rosa Rodriguez, Victor Toledano, Berta Rodés
Background: Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment. The abundance level of various chromatin-modifying enzymes produces these alterations and affects both the provirus and cellular gene expression. Here, we investigated potential changes in enzyme expression and global DNA methylation in chronically infected individuals with HIV-1 and compared these changes with non-HIV infected individuals...
2018: Clinical Epigenetics
Sheraz Khan, Mazhar Iqbal, Muhammad Tariq, Shahid M Baig, Wasim Abbas
HIV-1 latency allows the virus to persist until reactivation, in a transcriptionally silent form in its cellular reservoirs despite the presence of effective cART. Such viral persistence represents a major barrier to HIV eradication since treatment interruption leads to rebound plasma viremia. Polycomb group (PcG) proteins have recently got a considerable attention in regulating HIV-1 post-integration latency as they are involved in the repression of proviral gene expression through the methylation of histones...
2018: Clinical Epigenetics
Jan Kramer, Veronika Désor, Steffen Brunst, Sandra K Wittmann, Jörn Lausen, Jan Heering, Anna Proschak, Ewgenij Proschak
The protein arginine N-methyltransferase 6 (PRMT6) is overexpressed in a variety of different cancer types and plays a role in human immunodeficiency virus (HIV) infections. Furthermore, the PRMT6 activity might also influence the pathogenesis of neurodegenerative, inflammatory, and cardiovascular diseases, whereby it becomes an interesting target for drug development. Previously reported activity assays for PRMT6 activity are either expensive, time-consuming or use radioactive substrates. To overcome these challenges, we developed a coupled fluorescence-based activity assay using recombinant PRMT6 expressed in E...
April 15, 2018: Analytical Biochemistry
Futoshi Taura, Miu Iijima, Fumiya Kurosaki
Daurichromenic acid (DCA) is a meroterpenoid with anti-HIV activities that is isolated from Rhododendron dauricum L. We recently reported that DCA is biosynthesized and accumulated in the apoplast of glandular scales attached on the surface of young leaves of R. dauricum. In the present study, we confirmed that a cell suspension culture of R. dauricum could not produce DCA and its precursor grifolic acid even after elicitation with methyl jasmonate and β-cyclodextrin. In addition, exogenous supplementation of DCA and grifolic acid effectively induced cell death in the same culture, with apoptosis-associated phenomena such as cytoplasmic shrinkage, chromatin condensation, and genomic DNA degradation...
January 2, 2018: Plant Signaling & Behavior
Jolien Blokken, Jan De Rijck, Frauke Christ, Zeger Debyser
Lens epithelium-derived growth factor p75 (LEDGF/p75), a transcriptional co-activator, plays an important role in tethering protein complexes to the chromatin. Through this tethering function LEDGF/p75 is implicated in a diverse set of human diseases including HIV infection and mixed lineage leukemia, an aggressive form of cancer with poor prognosis. Here we provide an overview of recent progress in resolving protein-protein and protein-chromatin interaction mechanisms of LEDGF/p75. This review will focus on two well-characterized domains, the PWWP domain and the integrase binding domain (IBD)...
June 2017: Drug Discovery Today. Technologies
Jing Yin, Xin Li, Yaguang Zhan, Ying Li, Ziyue Qu, Lu Sun, Siyao Wang, Jie Yang, Jialei Xiao
BACKGROUND: Birch (Betula platyphylla Suk.) contains triterpenoids with anti-HIV and anti-tumor pharmacological activities. However, the natural abundance of these triterpenoids is low, and their chemical synthesis is costly. Transcription factors have the ability to regulate the metabolite pathways of triterpenoids via multi-gene control, thereby improving metabolite yield. Thus, transcription factors have the potential to facilitate the production of birch triterpenoids. Plant bHLH (basic helix-loop-helix) transcription factors play important roles in stress response and secondary metabolism...
November 21, 2017: BMC Plant Biology
Daniela Boehm, Melanie Ott
A successful HIV cure strategy may require reversing HIV latency to purge hidden viral reservoirs or enhancing HIV latency to permanently silence HIV transcription. Epigenetic modifying agents show promise as antilatency therapeutics in vitro and ex vivo, but also affect other steps in the viral life cycle. In this review, we summarize what we know about cellular DNA and protein methyltransferases (PMTs) as well as demethylases involved in HIV infection. We describe the biology and function of DNA methyltransferases, and their controversial role in HIV infection...
November 2017: AIDS Research and Human Retroviruses
Ilaria Morbioli, Vanessa Porkolab, Andrea Magini, Alessandro Casnati, Franck Fieschi, Francesco Sansone
DC-SIGN is a receptor protruded from the membrane of immature dendritic cells (DCs) that participates in the activation of the immune response through the recognition of pathogen-associated molecular patterns (PAMPs). On the other hand, HIV exploits the interaction between high-mannose structures of its envelope glycoprotein gp120 and DC-SIGN to be transported towards and infect T-cells. DC-SIGN is involved in the recognition process in the form of a tetramer and the multiple exposition of carbohydrate recognition sites (CRSs) is amplified by the formation on the DCs membrane of patches of tetramers...
October 31, 2017: Carbohydrate Research
Ping Su, Hongyu Guan, Yifeng Zhang, Xing Wang, Linhui Gao, Yujun Zhao, Tianyuan Hu, Jiawei Zhou, Baowei Ma, Lichan Tu, Yuru Tong, Luqi Huang, Wei Gao
Tripterygium wilfordii produces not only ent -kaurene, which is an intermediate of gibberellin (GA) biosynthesis in flowering plants, but also 16α-hydroxy- ent -kaurane, whose physiological role has not been characterized. The two compounds are biosynthesized from the universal diterpenoid precursor ( E , E , E )-geranylgeranyl diphosphate (GGPP) by diterpene synthases, which have been discovered and functionally characterized in T. wilfordii . Here, we described the functional characterization of four cytochrome P450 reductases (TwCPR) and one ent -kaurene oxidase (TwKO)...
2017: Frontiers in Plant Science
Khethobole C Sekgota, Swarup Majumder, Michelle Isaacs, Dumisani Mnkandhla, Heinrich C Hoppe, Setshaba D Khanye, Frederik H Kriel, Judy Coates, Perry T Kaye
A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.
September 22, 2017: Bioorganic Chemistry
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