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Scott Ledger, Annett Howe, Stuart Turville, Anupriya Aggarwal, Borislav Savkovic, Andrew Ong, Orit Wolstein, Maureen Boyd, Michelle Millington, Paul R Gorry, John M Murray, Geoff Symonds
The gene therapeutic Cal-1 comprises the anti-HIV agents: sh5, a short hairpin RNA to CCR5 that down-regulates CCR5 expression; and maC46 (C46), a peptide that inhibits viral fusion with the cell membrane. These constructs were assessed for inhibition of viral replication and selective cell expansion in a number of settings. METHODS: HIV replication, selective outgrowth and cell surface viral binding were analysed with a single cycle infection assay of 6 pseudotyped HIV strains and a static and longitudinal passaging of MOLT4/CCR5 cells with HIV...
February 10, 2018: Journal of Gene Medicine
Tao Gao, Zhiyuan Shen, Chao Ma, Yun Li, Xiangfeng Kang, Moyi Sun
PURPOSE: Perineural invasion (PNI) is a hallmark of salivary adenoid cystic carcinoma (SACC) and represents an important risk factor for local recurrence and poor survival. However, the mechanism of PNI has yet to be explored. We sought to examine the CCL5-CCR5 ligand-receptor interaction between nerves and SACC cells. MATERIALS AND METHODS: CCL5/CCR5 expression was determined by immunohistochemistry in SACC tissue specimens. The correlations between CCL5/CCR5 expression and clinicopathologic features were investigated...
February 20, 2018: Journal of Oral and Maxillofacial Surgery
Cheleka A M Mpande, One B Dintwe, Munyaradzi Musvosvi, Simbarashe Mabwe, Nicole Bilek, Mark Hatherill, Elisa Nemes, Thomas J Scriba
Background: Maintenance of long-lasting immunity is thought to depend on stem cell memory T cells (TSCM ), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (TCM ) or effector (TEFF ) T cells. Our knowledge of TSCM derives primarily from studies of virus-specific CD8+ TSCM . We aimed to determine if infection with Mycobacterium tuberculosis ( M. tb ), the etiological agent of tuberculosis, generates antigen-specific CD4+ TSCM and to characterize their functional ontology...
2018: Frontiers in Immunology
Tafadzwa Mlambo, Sandra Nitsch, Markus Hildenbeutel, Marianna Romito, Maximilian Müller, Claudia Bossen, Sven Diederichs, Tatjana I Cornu, Toni Cathomen, Claudio Mussolino
Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression...
March 10, 2018: Nucleic Acids Research
Stefan Gahbauer, Kristyna Pluhackova, Rainer A Böckmann
Chemokine receptors, a subclass of G protein coupled receptors (GPCRs), play essential roles in the human immune system, they are involved in cancer metastasis as well as in HIV-infection. A plethora of studies show that homo- and heterodimers or even higher order oligomers of the chemokine receptors CXCR4, CCR5, and CCR2 modulate receptor function. In addition, membrane cholesterol affects chemokine receptor activity. However, structural information about homo- and heterodimers formed by chemokine receptors and their interplay with cholesterol is limited...
March 12, 2018: PLoS Computational Biology
Tafadzwa Mlambo, Marianna Romito, Tatjana I Cornu, Claudio Mussolino
The development of tools which allow for the precise alterations of the epigenetic landscape in desired genomic locations presents exciting possibilities toward further understanding how gene expression is regulated and opportunities to harness these properties for therapeutic purposes. In contrast to gene knockout strategies, targeted epigenome modifications, such as editing of DNA methylation, can mediate gene expression modulation without changing the genomic sequence. Thereby, in a therapeutic context, this strategy may offer a safer route as compared to gene disruption using designer nucleases that, to reach high efficiencies, relies on the occurrence of random mutations to inactivate the target gene...
2018: Methods in Molecular Biology
Le Guo, Xi-Qiu Xu, Li Zhou, Run-Hong Zhou, Xu Wang, Jie-Liang Li, Jin-Biao Liu, Hang Liu, Biao Zhang, Wen-Zhe Ho
As a rich source of CD4+ T cells and macrophages, the gastrointestinal (GI) tract is a major target site for HIV infection. The interplay between GI-resident macrophages and intestinal epithelial cells (IECs) constitutes an important element of GI innate immunity against pathogens. In this study, we investigated whether human IECs have the ability to produce antiviral factors that can inhibit HIV infection of macrophages. We demonstrated that IECs possess functional toll-like receptor 3 (TLR3), the activation of which resulted in induction of key interferon (IFN) regulatory factors (IRF3 and IRF7), IFN-β, IFN-λ, and CC chemokines (MIP-1α, MIP-1β, RANTES), the ligands of HIV entry co-receptor CCR5...
2018: Frontiers in Immunology
Matthew Wiest, Katherine Upchurch, Wenjie Yin, Jerome Ellis, Yaming Xue, Bobby Lanier, Mark Millard, HyeMee Joo, SangKon Oh
Background: T cells play a central role in chronic inflammation in asthma. However, the roles of individual subsets of T cells in the pathology of asthma in patients remain to be better understood. Methods: We investigated the potential signatures of T cell subset phenotypes in asthma using fresh whole blood from adult atopic asthma patients (n = 43) and non-asthmatic control subjects (n = 22). We further assessed their potential clinical implications by correlating asthma severity...
2018: Allergy, Asthma, and Clinical Immunology
Andreia Monteiro, Catarina Cruto, Pedro Rosado, António Martinho, Luiza Rosado, Mafalda Fonseca, Artur Paiva
We characterized circulating gamma-delta T cells in relapsing-remitting multiple sclerosis (RRMS) patients, during remission and relapse phases. In relapse, we observed a decrease of circulating CCR5+ γδ TEMRA cell subset, together with a decrease in EOMES and granzyme B mRNA expression in γδ T cells, suggesting a reduction of the cytotoxic potential of this subset. Moreover, we also found a higher frequency of IFNγ+ γδ T cells, which may indicate that these cells are assuming a more regulatory function associated to a Th1 profile...
February 24, 2018: Journal of Neuroimmunology
Cristina Clemente, Cristina Rius, Laura Alonso-Herranz, Mara Martín-Alonso, Ángela Pollán, Emilio Camafeita, Fernando Martínez, Rubén A Mota, Vanessa Núñez, Cristina Rodríguez, Motoharu Seiki, José Martínez-González, Vicente Andrés, Mercedes Ricote, Alicia G Arroyo
Matrix metalloproteinases are involved in vascular remodeling. Little is known about their immune regulatory role in atherosclerosis. Here we show that mice deficient for MT4-MMP have increased adherence of macrophages to inflamed peritonea, and larger lipid deposits and macrophage burden in atherosclerotic plaques. We also demonstrate that MT4-MMP deficiency results in higher numbers of patrolling monocytes crawling and adhered to inflamed endothelia, and the accumulation of Mafb+ apoptosis inhibitor of macrophage (AIM)+ macrophages at incipient atherosclerotic lesions in mice...
March 2, 2018: Nature Communications
Minjun Yang, Ruina Zhi, Lu Lu, Mingxin Dong, Yuzhu Wang, Fang Tian, Minjie Xia, Jingying Hu, Qiuyun Dai, Shibo Jiang, Weihua Li
B07 is a small-molecule CCR5 antagonist-based HIV-1 entry inhibitor that is being developed as an anti-HIV microbicide for preventing sexual transmission of HIV. Here we evaluated its spermicidal and contraceptive potential, including sperm motility, plasma membrane integrity, and contraceptive efficacy tested in rabbits. We found that B07 inhibited sperm motility and movement patterns in a concentration- and time-dependent manner. Within 30 min, B07 induced sperm immobilization with the minimum 100% effective concentration and median effective concentration of 640...
February 26, 2018: European Journal of Pharmaceutical Sciences
Manickam Ashokkumar, Shambhu G Aralaguppe, Srikanth P Tripathy, Luke Elizabeth Hanna, Ujjwal Neogi
Adequate information on the precise molecular and biological composition of the viral strains that establish HIV-infection in the human host will provide effective means of immunization against HIV-infection. In an attempt to identify and differentiate the biological properties and infectious potential of the transmitted founder (TF) virus from the population of the early transmitted virus, patient-derived 250 envelope glycoprotein, gp120 were cloned in pMN-K7-Luc-IRESs-NefΔgp120 to obtain chimeric viruses...
February 28, 2018: Journal of Virology
Long Feng, Wuhao Lu, Yunyun Ma, Wentao Guo, Yuanyuan Wang, Qianqian Sun, Jianbo Wu, Guoqiang Zhao, Xiaoli Zhang
Acquired immunodeficiency syndrome (AIDS) is a serious worldwide disease caused by infection with the human immunodeficiency virus (HIV). C-C chemokine receptor 5 (CCR5) and C-X-C chemokine receptor 4 (CXCR4) are important coreceptors mediating HIV-1 cell entry. Many new anti-HIV drugs are currently in preclinical and clinical trials; however, drug development has proceeded slowly partly because of the lack of a high-throughput system to screen these drugs. Here, we describe the development of a novel dual-luciferase assay using a CCR5/CXCR4 promoter-driven firefly and Renilla luciferase vector (pGL4...
February 23, 2018: Journal of Virological Methods
Elaine Tseng, Gwendolyn D Fate, Gregory S Walker, Theunis C Goosen, R Scott Obach
Maraviroc (MVC) is an CCR5 co-receptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 (HIV-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...
February 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sarah Auclair, Fengliang Liu, Qingli Niu, Wei Hou, Gavin Churchyard, Cecilia Morgan, Nicole Frahm, Sorachai Nitayaphan, Punnee Pitisuthithum, Supachai Rerks-Ngarm, Jason T Kimata, Lynn Soong, Genoveffa Franchini, Merlin Robb, Jerome Kim, Nelson Michael, Haitao Hu
The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector-specific CD4 T cells in the HVTN204 trial...
February 23, 2018: PLoS Pathogens
Chang Hoon Lee, Hongwei H Zhang, Satya P Singh, Lily Koo, Juraj Kabat, Hsinyi Tsang, Tej Pratap Singh, Joshua M Farber
Many mediators and regulators of extravasation by bona fide human memory-phenotype T cells remain undefined. Mucosal-associated invariant T (MAIT) cells are innate-like, anti-bacterial cells that we found excelled at crossing inflamed endothelium. They displayed abundant selectin ligands, with high expression of FUT7 and ST3GAL4 , and expressed CCR6, CCR5, and CCR2, which played non-redundant roles in trafficking on activated endothelial cells. MAIT cells selectively expressed CCAAT/enhancer-binding protein delta (C/EBPδ)...
February 22, 2018: ELife
Remo Castro Russo, Benedetta Savino, Massimiliano Mirolo, Chiara Buracchi, Giovanni Germano, Achille Anselmo, Luca Zammataro, Fabio Pasqualini, Alberto Mantovani, Massimo Locati, Mauro M Teixeira
RATIONALE: Chemokines coordinate lung inflammation and fibrosis by acting on chemokine receptors expressed on leukocytes and other cell types. Atypical chemokine receptors (ACKRs) bind, internalize and degrade chemokines, tuning homeostasis and immune responses. ACKR2 recognizes and decreases levels of inflammatory CC chemokines. The role of ACKR2 in fibrogenesis is unknown. OBJECTIVE: Investigate the role of ACKR2 in the context of pulmonary fibrosis. METHODS: The effects of ACKR2 expression and deficiency during inflammation and fibrosis were analyzed using a bleomycin-model of fibrosis, ACKR2-deficient mice, bone marrow chimeras and antibody-mediated leukocyte depletion...
February 22, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Yair Sapir, Alon Vitenshtein, Yiftah Barsheshet, Yaniv Zohar, Gizi Wildbaum, Nathan Karin
No abstract text is available yet for this article.
February 21, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Aleksandra Butrym, Ilona Kryczek, Dorota Dlubek, Emilia Jaskula, Andrzej Lange, Artur Jurczyszyn, Grzegorz Mazur
Chemokines are small proteins, that regulate cell migration in many physiological and pathologic processes in human body. They are also responsible for cancer progression. CC chemokine receptor 5 (CCR5) is responsible for cell recruitment in inflammation and may be involved in antitumor immune response controlling. Aberrant CCR5 can be found in different kind of cancers, not only hematological, but also solid tumors. Non-Hodgkin lymphomas consist of many lymphoma subtypes. They predominantly derive from B cells and can have very heterogenous clinical course...
January 10, 2018: Current Problems in Cancer
Frank Tacke
Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is associated with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis. Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis...
February 16, 2018: Expert Opinion on Investigational Drugs
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