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Antiviral Research

Smriti Kala, Birgit Watson, Jeremy Guijun Zhang, Eszter Papp, Monica Guzman Lenis, Michelle Dennehy, D William Cameron, P Richard Harrigan, Lena Serghides
Animal models can be useful tools for the study of HIV antiretroviral (ARV) safety/toxicity in pregnancy and the mechanisms that underlie ARV-associated adverse events. The utility and translatability of animal model-based ARV safety/toxicity data is improved if ARVs are tested in clinically relevant concentrations. The objective of this work was to improve the clinical relevance of our mouse pregnancy model of ARV toxicity, by determining the doses of currently prescribed ARV regimens that would yield human therapeutic plasma concentrations...
September 17, 2018: Antiviral Research
Ryan Aguanno, Ahmed ElIdrissi, Amgad A Elkholy, Peter Ben Embarek, Emma Gardner, Rebecca Grant, Heba Mahrous, Mamunur Rahman Malik, Gounalan Pavade, Sophie VonDobschuetz, Lidewij Wiersma, Maria D Van Kerkhove
This article summarizes progress in research on Middle East Respiratory Syndrome (MERS) since a FAO-OIE-WHO Global Technical Meeting held at WHO Headquarters in Geneva on 25-27 September 2017. The meeting reviewed the latest scientific findings and identified and prioritized the global activities necessary to prevent, manage and control the disease. Critical needs for research and technical guidance identified during the meeting have been used to update the WHO R&D MERS-CoV Roadmap for diagnostics, therapeutics and vaccines and a broader public health research agenda...
September 17, 2018: Antiviral Research
William J Britt, Mark N Prichard
The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today's standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease...
September 15, 2018: Antiviral Research
Yacine Abed, Véronique Tu, Julie Carbonneau, Liva Checkmahomed, Marie-Christine Venable, Clément Fage, Marie-Ève-Hamelin, Simon F Dufresne, Gary Kobinger, Guy Boivin
After 6 years of circulation in humans, a novel antigenic variant of influenza A(H1N1)pdm09 (i.e., A/Michigan/45/2015) emerged in 2015-16 and has predominated thereafter worldwide. Herein, we compared in vitro and in vivo properties of 2016 wild-type (WT) A/Michigan/45/15-like isolate and its H275Y neuraminidase (NA) variant to the original A/California/07/09-like counterparts. The H275Y mutation induced comparable levels of resistance to oseltamivir and peramivir without altering zanamivir susceptibility in both 2009 and 2016 isolates...
September 13, 2018: Antiviral Research
Mugdha Vasireddi, Albert Crum, Harold May, David Katz, Julia Hilliard
We investigated the effects of a specific free-form amino formulation on Zika virus replication in two different cell culture model systems, one representative of humans and the other of Old World primates from whom Zika virus was first isolated. Here we present data demonstrating that the formulation of the specific free-form amino acids (FFAAP), comprising cystine, glycine, and a glutamate source, along with a minute concentration of selenium inhibited Zika virus replication by up to 90% with an ED90 (effective dose at which 90% of a dose of Zika virus was inhibited) of 2...
September 11, 2018: Antiviral Research
Alexander W Tarr, Matthijs Backx, Mohamed R Hamed, Richard A Urbanowicz, C Patrick McClure, Richard J P Brown, Jonathan K Ball
Global eradication of hepatitis C virus (HCV) infection will require an efficacious vaccine capable of eliciting protective immunity against genetically diverse HCV strains. Natural spontaneous resolution of HCV infection is associated with production of broadly-neutralizing antibodies targeting the HCV glycoproteins E1 and E2. As such, production of cross-neutralizing antibodies is an important endpoint for experimental vaccine trials. Varying success generating cross-neutralizing antibodies has been achieved with immunogens derived from naturally-occurring HCV strains...
September 11, 2018: Antiviral Research
Andrii Slonchak, Alexander A Khromykh
The common feature of flaviviral infection is the accumulation of abundant virus-derived noncoding RNA, named flaviviral subgenomic RNA (sfRNA) in infected cells. This RNA represents a product of incomplete degradation of viral genomic RNA by the cellular 5'-3' exoribonuclease XRN1 that stalls at the conserved highly structured elements in the 3' untranslated region (UTR). This mechanism of sfRNA generation was discovered a decade ago and since then sfRNA has been a focus of intense research. The ability of flaviviruses to produce sfRNA was shown to be evolutionary conserved in all members of Flavivirus genus...
September 11, 2018: Antiviral Research
Shuo Wu, Yue Luo, Usha Viswanathan, John Kulp, Junjun Cheng, Zhanying Hu, Qifang Xu, Yan Zhou, Guo-Zhong Gong, Jinhong Chang, Yuhuan Li, Ju-Tao Guo
Native agarose gel electrophoresis-based particle gel assay has been commonly used for examination of hepatitis B virus (HBV) capsid assembly and pregenomic RNA encapsidation in HBV replicating cells. Interestingly, treatment of cells with several chemotypes of HBV core protein allosteric modulators (CpAMs) induced the assembly of both empty and DNA-containing capsids with faster electrophoresis mobility. In an effort to determine the physical basis of CpAM-induced capsid mobility shift, we found that the surface charge, but not the size, of capsids is the primary determinant of electrophoresis mobility...
September 7, 2018: Antiviral Research
Angelica Corcuera, Katharina Stolle, Stefan Hillmer, Stefan Seitz, Ji-Young Lee, Ralf Bartenschlager, Alexander Birkmann, Andreas Urban
One of the most promising viral targets in current hepatitis B virus (HBV) drug development is the core protein due to its multiple roles in the viral life cycle. Here we investigated the differences in the mode of action and antiviral activity of representatives of six different capsid assembly modifier (CAM) scaffolds: three from the well-characterized scaffolds heteroarylpyrimidine (HAP), sulfamoylbenzamide (SBA), and phenylpropenamide (PPA), and three from novel scaffolds glyoxamide-pyrrolamide (GPA), pyrazolyl-thiazole (PT), and dibenzo-thiazepin-2-one (DBT)...
July 20, 2018: Antiviral Research
Annasaheb Kolpe, Bert Schepens, Liang Ye, Peter Staeheli, Xavier Saelens
Influenza represents a global public health threat. Currently available influenza vaccines are effective against strain-matched influenza A and B viruses but do not protect against novel pandemic viruses. Vaccine candidates that target conserved B or T cell epitopes of influenza viruses could circumvent this shortcoming. The conserved extracellular domain of matrix protein 2 (M2e) of influenza A is an example of such a broadly protective vaccine candidate. Protection by M2e-based vaccine candidates largely depends on M2e-specific IgG antibodies...
October 2018: Antiviral Research
M Shea O'Brien, Kylie C Markovich, Dean Selleseth, Alexa V DeVita, Phiroze Sethna, Brian G Gentry
Human cytomegalovirus (HCMV) can cause severe disease in patients with compromised or immature immune systems. Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance. Given that many of these drugs have the same viral target (HCMV-encoded DNA polymerase), cross-resistance is relatively common. The primary means to combat drug resistance is combination pharmacotherapy using therapeutics with different molecular mechanisms of action with the expectation that those combinations result in an additive or synergistic enhancement of effect; combinations that result in antagonism can, in many cases, be detrimental to the outcome of the patient...
October 2018: Antiviral Research
H J Florin, R Snoeck, B Van Cleynenbreugel, M Albersen
Condylomata acuminata (CA) or anogenital warts are benign proliferative lesions caused by low-risk human papillomaviruses (HPV). Treating CA can be very frustrating for patients and clinicians due to the high recurrence rates. Immunosuppression is associated with larger size of CA that are more frequently resistant to treatment. Surgical approaches tend to be poorly effective in the long-term because of high recurrence rates related to the persistence of HPV-infected cells. In our search to find an agent to treat intraurethral CA with minor or no side effects, we evaluated intraurethral cidofovir in two male patients, who were under immunosuppressing therapy due to organ transplantation and suffered from extensive urethral HPV lesions...
October 2018: Antiviral Research
Nakyung Lee, David Shum, Alexander König, Hichul Kim, Jinyeong Heo, Saehong Min, Jihye Lee, Yoonae Ko, Inhee Choi, Honggun Lee, Constantin Radu, Thomas Hoenen, Ji-Young Min, Marc P Windisch
The massive epidemic of Ebola virus disease (EVD) in West Africa, followed in recent months by two outbreaks in the Democratic Republic of the Congo, underline the importance of this severe disease. Because Ebola virus (EBOV) must be manipulated under biosafety level 4 (BSL4) containment, the discovery and development of virus-specific therapies have been hampered. Recently, a transient transfection-based transcription- and replication competent virus-like particle (trVLP) system was described, enabling modeling of the entire EBOV life cycle under BSL2 conditions...
October 2018: Antiviral Research
Bidisha Mitra, Roshan J Thapa, Haitao Guo, Timothy M Block
Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself...
October 2018: Antiviral Research
Priya Luthra, Jacinth Naidoo, Colette A Pietzsch, Sampriti De, Sudip Khadka, Manu Anantpadma, Caroline G Williams, Megan R Edwards, Robert A Davey, Alexander Bukreyev, Joseph M Ready, Christopher F Basler
Specific host pathways that may be targeted therapeutically to inhibit the replication of Ebola virus (EBOV) and other emerging viruses remain incompletely defined. A screen of 200,000 compounds for inhibition of an EBOV minigenome (MG) assay that measures the function of the viral polymerase complex identified as hits several compounds with an amino-tetrahydrocarbazole scaffold. This scaffold was structurally similar to GSK983, a compound previously described as having broad-spectrum antiviral activity due to its impairing de novo pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase (DHODH)...
October 2018: Antiviral Research
Hsu-Feng Chu, Chiao-Che Chen, David C Moses, Yau-Hung Chen, Chao-Hsiung Lin, Ying-Chieh Tsai, Chi-Yuan Chou
Porcine epidemic diarrhea virus (PEDV) is a coronavirus (CoV) discovered in the 1970s that infects the intestinal tract of pigs, resulting in diarrhea and vomiting. It can cause extreme dehydration and death in neonatal piglets. In Asia, modified live attenuated vaccines have been used to control PEDV infection in recent years. However, a new strain of PEDV that belongs to genogroup 2a appeared in the USA in 2013 and then quickly spread to Canada and Mexico as well as Asian and European countries. Due to the less effective protective immunity provided by the vaccines against this new strain, it has caused considerable agricultural and economic loss worldwide...
October 2018: Antiviral Research
Chuan Xia, Young-Jin Seo, Caleb J Studstill, Madhuvanthi Vijayan, Jennifer J Wolf, Bumsuk Hahm
Influenza continues to pose a threat to public health by causing illness and mortality in humans. Discovering host factors that regulate influenza virus propagation is vital for the development of novel drugs. We have previously reported that sphingosine kinase (SphK) 1 promotes influenza A virus (IAV) replication in vitro. Here we demonstrate that the other isoform of SphK, SphK2 promotes the replication of influenza A virus (IAV) in cultured cells, and temporary inhibition of SphK1 or SphK2 enhances the host defense against influenza in mice...
October 2018: Antiviral Research
Richa Sood, Naveen Kumar, Sandeep Bhatia, Khangembam Victoria Chanu, Chhedi Lal Gupta, Atul Kumar Pateriya, Anamika Mishra, Rekha Khandia, Namrata Mawale, Vijendra Pal Singh
We tested 65 highly pathogenic avian influenza (HPAI) A(H5N1) viruses, isolated from avian species in India between 2006 and 2015, for susceptibility to the FDA approved neuraminidase (NA) inhibitors (NAIs), oseltamivir and zanamivir using a phenotypic fluorescence-based assay. The overall incidence of resistant variants among HPAI A(H5N1) viruses was 7.69% (5/65). The NA inhibition assay identified 3 viruses resistant to oseltamivir (N294S substitution, N2 numbering) and 2 cross-resistant to oseltamivir and zanamivir (E119A or I117V+E119A substitutions), all of which belonged to hemagglutinin (HA) clade 2...
October 2018: Antiviral Research
Meike H van der Ree, Louis Jansen, Matthijs R A Welkers, Hendrik W Reesink, K Anton Feenstra, Neeltje A Kootstra
BACKGROUND: We aimed to identify HBc amino acid differences between subgroups of chronic hepatitis B (CHB) patients. METHODS: Deep sequencing of HBc was performed in samples of 89 CHB patients (42 HBeAg positive, 47 HBeAg negative). Amino acid types were compared using Sequence Harmony to identify subgroup specific sites between HBeAg-positive and -negative patients, and between patients with combined response and non-response to peginterferon/adefovir combination therapy...
October 2018: Antiviral Research
Lai Wei, Masao Omata, Young-Suk Lim, Qing Xie, Jin Lin Hou, Jidong Jia, Charlotte Hedskog, Ross Martin, Brian Doehle, Jenny Yang, Shampa De-Oertel, Benedetta Massetto, Kathryn Kersey, Diana M Brainard, Evguenia Svarovskaia, Hongmei Mo, Kwang-Hyub Han, Masashi Mizokami, Zhongping Duan
BACKGROUND & AIMS: Resistance associated substitutions (RAS) can reduce the efficacy of some direct-acting antiviral HCV regimens. Here, prevalence of RAS in genotype (GT) 1b, 2, 3, and 6 HCV-infected patients from Asian counties, North America and Europe are described and compared. METHODS: Pretreatment HCV RAS were assessed with 15% cutoff from patients enrolled in clinical trials of sofosbuvir-containing regimens in Mainland China, Japan, Korea, and India...
October 2018: Antiviral Research
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