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Rawad Elias, Kevan Hartshorn, Osama Rahma, Nina Lin, Jennifer E Snyder-Cappione
The advent of immune checkpoint inhibitors (ICIs) has changed the landscape of cancer treatment. Older adults represent the majority of cancer patients; however, direct data evaluating ICIs in this patient population is lacking. Aging is associated with changes in the immune system known as "immunosenescence" that could impact the efficacy and safety profile of ICIs. In this paper, we review aging-associated changes in the immune system as they may relate to cancer and immunotherapy, with mention of the effect of chronic viral infections and frailty...
August 2018: Seminars in Oncology
Sudha Singh, Anvita Gupta Malhotra, Mohit Jha, Khushhali Menaria Pandey
Recently three FDA approved existing drugs, namely-Oseltamivir, Peramivir and Zanamivir, used against Neuraminidase (NA) for the inhibitory effect on the process of viral progeny release to inhibit infection. All NA subtypes has been divided into two groups (Group 1 and Group 2) based on phylogenetic study. Oseltamivir and Zanamivir drugs are designed for Group 2 NA but are also used against 2009 H1N1 NA that lies in Group 1. There is no specific drug available for H1N1 and, consequently, there is an urgent requirement for the same...
December 2018: Virusdisease
Mitesh Patel, Manojkumar Sachidanandan, Mohd Adnan
Serine/arginine protein kinase 1 (SRPK1); a versatile functional moonlighting protein involved in varied cellular activities comprised of cell cycle progression, innate immune response, chromatin reorganization, negative and positive regulation of viral genome replication, protein amino acid phosphorylation, regulation of numerous mRNA-processing pathways, germ cell development as well as inflammation due to acquaintances with many transcription factors and signaling pathways. Several diseases including cancer have been associated with dysregulation of SRPK1...
December 8, 2018: Molecular Biology Reports
Hotma Martogi Lorensi Hutapea, Yustinus Maladan, Widodo
Integrase (IN) plays an essential role in HIV-1 replication, by mediating integration of the viral genome into the host cell genome. IN is a potential target of antiretroviral (ARV) therapeutic drugs such as ALLINI, Raltegravir (RAL), and Elvitegravir (EVG). The effect of IN polymorphisms on its structure and binding affinity to the integrase inhibitors (INIs) is not well understood. The goal of this study was to examine the effect of IN polymorphisms on its tertiary structure and binding affinities to INIs using computational approaches...
December 2018: Heliyon
Xiaohong Huang, Shina Wei, Songwei Ni, Youhua Huang, Qiwei Qin
The ubiquitin-proteasome system (UPS) serves as the major intracellular pathway for protein degradation and plays crucial roles in several cellular processes. However, little is known about the potential actions of the UPS during fish virus infection. In this study, we elucidated the possible roles of UPS in the life cycle of Singapore grouper iridovirus (SGIV); a large DNA virus that usually causes serious systemic diseases with high mortality in groupers. Data from transcriptomic analysis of differentially expressed genes illustrated that expression of 65 genes within the UPS pathway, including ubiquitin encoding, ubiquitination, deubiquitination, and proteasome, were up- or down-regulated during SGIV infection...
2018: Frontiers in Microbiology
Radiana T Trifonova, Brooke Bollman, Natasha S Barteneva, Judy Lieberman
The importance of myeloid cells in HIV transmission in the female genital tract is uncertain. Because it is difficult to study the early events in HIV transmission in humans, most of our knowledge is based on animal models of SIV infection in Rhesus macaques and more recently HIV infection in humanized mice. However, these models may not accurately recapitulate transmission in the human genital tract. CD14+ myeloid cells are the most abundant hematopoietic cells in the human cervical mucosa, comprising 40-50% of CD45+ mononuclear cells...
2018: Frontiers in Immunology
Jérôme Gouttenoire, Angela Pollán, Laurence Abrami, Noémie Oechslin, Johann Mauron, Maxime Matter, Joël Oppliger, Dagmara Szkolnicka, Viet Loan Dao Thi, F Gisou van der Goot, Darius Moradpour
Hepatitis E virus (HEV) is a positive-strand RNA virus encoding 3 open reading frames (ORF). HEV ORF3 protein is a small, hitherto poorly characterized protein involved in viral particle secretion and possibly other functions. Here, we show that HEV ORF3 protein forms membrane-associated oligomers. Immunoblot analyses of ORF3 protein expressed in cell-free vs. cellular systems suggested a posttranslational modification. Further analyses revealed that HEV ORF3 protein is palmitoylated at cysteine residues in its N-terminal region, as corroborated by 3H-palmitate labeling, the investigation of cysteine-to-alanine substitution mutants and treatment with the palmitoylation inhibitor 2-bromopalmitate (2-BP)...
December 10, 2018: PLoS Pathogens
Weiwei Mu, Adam W Bartlett, Torsak Bunupuradah, Kulkanya Chokephaibulkit, Nagalingeswaran Kumarasamy, Penh Sun Ly, Rawiwan Hansudewechakul, Nguyen Van Lam, Pagakrong Lumbiganon, Tavitiya Sudjaritruk, Thahira A Jamal Mohamed, Nik Khairulddin Nik Yusoff, Truong Huu Khanh, Do Chau Viet, Moy Siew Fong, Revathy Nallusamy, Nia Kurniati, Dewi Kumara Wati, Annette H Sohn, Azar Kariminia, Fujie Zhang
BACKGROUND: Virologic failure is a major threat to maintaining effective combination antiretroviral therapy, especially for children in need of lifelong treatment. With efforts to expand access to HIV viral load testing, our understanding of pediatric virologic failure is evolving. SETTING: An Asian cohort in16 pediatric HIV services across six countries. METHODS: From 2005-2014 patients aged <20 years who achieved virologic suppression and had subsequent viral load testing were included...
November 20, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Karen Cohen, Annemie Stewart, Andre P Kengne, Rory Leisegang, Marla Coetsee, Shavani Maharaj, Liezl Dunn, Michael Hislop, Gert van Zyl, Graeme Meintjes, Gary Maartens
BACKGROUND: Most adults with virological failure on second-line ART in resource limited settings have no major protease inhibitor (PI) resistance mutations. Therefore, empiric switches to third-line ART would waste resources. Genotypic antiretroviral resistance testing (GART) is expensive and has limited availability. A clinical prediction rule (CPR) for PI resistance could rationalise access to GART. SETTING: A private sector ART cohort, South Africa. METHODS: We identified adults with virologic failure on ritonavir-boosted lopinavir/atazanavir-based ART and GART...
November 20, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Anna Luganini, Giovanna Di Nardo, Luca Munaron, Gianfranco Gilardi, Alessandra Fiorio Pla, Giorgio Gribaudo
The human cytomegalovirus (HCMV) US12 gene family comprises a set of 10 contiguous genes (US12 to US21) with emerging roles in the regulation of virus cell tropism, virion composition, and immunoevasion. Of all of the US12 gene products, pUS21 shows the highest level of identity with two cellular transmembrane BAX inhibitor motif-containing (TMBIM) proteins: Bax inhibitor-1 and Golgi anti-apoptotic protein, both of which are involved in the regulation of cellular Ca2+ homeostasis and adaptive cell responses to stress conditions...
December 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
Randy Wouters, Szu-Yuan Pu, Mathy Froeyen, Eveline Lescrinier, Shirit Einav, Piet Herdewijn, Steven De Jonghe
Cyclin G-associated kinase (GAK) is a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, which regulates intracellular trafficking of dengue virus during early and late stages of the viral lifecycle. Previously, the discovery of isothiazolo[4,3-b]pyridines as potent and selective GAK inhibitors with promising antiviral activity was reported. In this manuscript, the synthesis of isothiazolo[4,3-b]pyridines with a carbon-linked substituent at position 3 is described by the application of regioselective Suzuki and Sonogashira coupling reactions...
November 28, 2018: European Journal of Medicinal Chemistry
Anuradha Balasubramanian, Rajendra Pilankatta, Tadahisa Teramoto, Ayyiliath M Sajith, Evaristus Nwulia, Amol Kulkarni, Radhakrishnan Padmanabhan
The dengue virus is considered to be a globally important human pathogen prevalent in tropical and subtropical regions of the world. According to a recent estimate, the disease burden due to DENV infections is ∼390 million infections per year globally in ∼100 countries including the southern US, Puerto Rico and Hawaii, resulting in nearly ∼25,000 deaths mostly among children. Despite the significant morbidity and mortality that results from DENV infections, there is currently no effective chemotherapeutic treatment for DENV infections...
December 6, 2018: Antiviral Research
Amrita Ojha, Angika Bhasym, Sriparna Mukherjee, Gowtham K Annarapu, Teena Bhakuni, Irshad Akbar, Tulika Seth, Naval K Vikram, Sudhanshu Vrati, Anirban Basu, Sankar Bhattacharyya, Prasenjit Guchhait
BACKGROUND: Activated platelets release cytokines/proteins including CXCL4 (PF4), CCL5 and fibrinopeptides, which regulate infection of several pathogenic viruses such as HIV, H1N1 and HCV in human. Since platelet activation is the hallmark of Dengue virus (DV) infection, we investigated the role of platelets in DV replication and also in a closely related Japanese Encephalitis virus (JEV). METHODS AND FINDINGS: Microscopy and PCR analysis revealed a 4-fold increase in DV replication in primary monocytes or monocytic THP-1 cells in vitro upon incubation with either DV-activated platelets or supernatant from DV-activated platelets...
December 5, 2018: EBioMedicine
Tatsuya Nagano, Motoko Tachihara, Yoshihiro Nishimura
Lung cancer is the leading cause of cancer death worldwide. Molecular targeted therapy has greatly advanced the field of treatment for non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancers. Indeed, gefitinib, which was the first molecular targeted therapeutic agent, has actually doubled the survival time of NSCLC patients. Vigorous efforts of clinicians and researchers have revealed that lung cancer develops through the activating mutations of many driver genes including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), and rearranged during transfection (RET) genes...
December 9, 2018: Current Cancer Drug Targets
Xuexiang Zhang, Junjun Cheng, Julia Ma, Zhanying Hu, Shuo Wu, Nicky Hwang, John Kulp, Yanming Du, Ju-Tao Guo, Jinhong Chang
Hepatitis B virus (HBV) core protein is a small protein with 183 amino acid residues and assembles the pre-genomic (pg) RNA and viral DNA polymerase to form nucleocapsids. During the last decades, several groups have reported HBV core protein allosteric modulators (CpAMs) with distinct chemical structures. CpAMs bind to the hydrophobic HAP pocket located at the dimer-dimer interface and induce allosteric conformational changes in the core protein subunits. While type I CpAMs, heteroaryldihydropyrimidine (HAP) derivatives, misdirect core protein dimers to assemble non-capsid polymers, Type II CpAMs, represented by sulfamoylbenzamides, phenylpropenamides and several other chemotypes, induce the assembly of empty capsids with global structural alterations and faster mobility in native agarose gel electrophoresis...
December 10, 2018: ACS Infectious Diseases
Yang Zhang, Jingyi Zou, Xiaomin Zhao, Zhenghong Yuan, Zhigang Yi
Daclatasvir (DCV) is a highly potent direct-acting antiviral that targets the non-structural protein 5A (NS5A) of hepatitis C virus (HCV) and has been used with great clinical success. Previous studies have demonstrated its impact on viral replication complex assembly. However, the precise mechanisms by which DCV impairs the replication complex assembly remains elusive. In this study, by using HCV subgenomic replicons and a viral replicase assembly surrogate system in which the HCV NS3-5B polyprotein is expressed to mimic the viral replicase assembly, we assessed the impact of DCV on the aggregation and tertiary structure of NS5A, the protein-protein interactions within the viral replicase and the quaternary structure of the viral replicase...
December 5, 2018: Journal of General Virology
Reneé de Waal, Richard Lessells, Anthony Hauser, Roger Kouyos, Mary-Ann Davies, Matthias Egger, Gilles Wandeler
The prevalence of pretreatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is >10% in many low-income countries. As a consequence, several sub-Saharan African countries have implemented, or are considering the introduction of, non-NNRTI-based first-line antiretroviral therapy (ART) for treatment-naïve and treatment-experienced patients. This is occurring at a time when ART programmes are expanding, in response to the World Health Organization guidelines, which recommend ART initiation regardless of CD4 cell count...
November 15, 2018: Journal of Virus Eradication
Jia Liu, Cong Yu, Jian-Fang Gui, Dai-Wen Pang, Qi-Ya Zhang
Reoviruses are non-enveloped viruses with wide host range, can cause serious infections in animals, plants and microorganism, e.g., aquareovirus, which is capable of causing serious haemorrhagic in aquatic animals. To date, the entry process of aquareovirus infection remains obscure. Real-time single-virus tracking are effective tools for exploring the details in viral infection process, which are crucial for understanding the pathogenic mechanism. Here, we used quantum dots-based single particle tracking technology combined with biochemical assays and ultrastructural observation to reveal unobservable infection steps and map dynamic interactions between a reovirus, Scophthalmus maximus reovirus (SMReV), and its host cell in real time...
2018: Frontiers in Microbiology
Hari Krishna Ananthula, Scott Parker, Erin Touchette, R Mark Buller, Gopi Patel, Daniel Kalman, Johanna S Salzer, Nadia Gallardo-Romero, Victoria Olson, Inger K Damon, Tessa Moir-Savitz, Larry Sallans, Milton H Werner, Catherine M Sherwin, Pankaj B Desai
BACKGROUND: Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for "repurposing" as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the "Animal Rule" to facilitate use of validated animal models for conducting anti-viral efficacy studies...
December 4, 2018: BMC Pharmacology & Toxicology
Junaid Raja, Johannes M Ludwig, Scott N Gettinger, Kurt A Schalper, Hyun S Kim
BACKGROUND: Immunotherapy is at the forefront of modern oncologic care. Various novel therapies have targeted all three layers of tumor biology: tumor, niche, and immune system with a range of promising results. One emerging class in both primary and salvage therapy is oncolytic viruses. This therapy offers a multimodal approach to specifically and effectively target and destroy malignant cells, though a barrier oncoviral therapies have faced is a limited therapeutic response to currently delivery techniques...
December 4, 2018: Journal for Immunotherapy of Cancer
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