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Journal: Viruses


Viruses have evolved various mechanisms to evade host immunity and ensure efficient viral replication and persistence. Several DNA tumor viruses modulate host DNA methyltransferases for epigenetic dysregulation of immune-related gene expression in host cells. The host immune responses suppressed by virus-induced aberrant DNA methylation are also frequently involved in antitumor immune responses. Here, we describe viral mechanisms and virus-host interactions by which DNA tumor viruses regulate host DNA methylation to evade antiviral immunity, which may contribute to the generation of an immunosuppressive microenvironment during cancer development. Recent trials of immunotherapies have shown promising results to treat multiple cancers; however, a significant number of non-responders necessitate identifying additional targets for cancer immunotherapies. Thus, understanding immune evasion mechanisms of cancer-causing viruses may provide great insights for reversing immune suppression to prevent and treat associated cancers.

Concepts: DNA methylation, Organism, Gene, Virus, Cancer, Gene expression, Immune system, DNA


The apolipoprotein B messenger RNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family of cytidine deaminases plays an important role in the innate immune response to viral infections by editing viral genomes. However, the cytidine deaminase activity of APOBEC3 enzymes also induces somatic mutations in host genomes, which may drive cancer progression. Recent studies of human papillomavirus (HPV) infection and disease outcome highlight this duality. HPV infection is potently inhibited by one family member, APOBEC3A. Expression of APOBEC3A and APOBEC3B is highly elevated by the HPV oncoproteins E6 and E7 during persistent virus infection and disease progression. Furthermore, there is a high prevalence of APOBEC3A and APOBEC3B mutation signatures in HPV-associated cancers. These findings suggest that induction of an APOBEC3-mediated antiviral response during HPV infection may inadvertently contribute to cancer mutagenesis and virus evolution. Here, we discuss current understanding of APOBEC3A and APOBEC3B biology in HPV restriction, evolution, and associated cancer mutagenesis.

Concepts: Bacteria, Infection, Disease, Mutation, Virus, Cancer, Human papillomavirus, Immune system


Prior to the discovery of the mimivirus in 2003, viruses were thought to be physically small and genetically simple. Mimivirus, with its ~750-nm particle size and its ~1.2-Mbp genome, shattered these notions and changed what it meant to be a virus. Since this discovery, the isolation and characterization of giant viruses has exploded. One of the more recently discovered giant viruses, Samba virus, is a Mimivirus that was isolated from the Rio Negro in the Brazilian Amazon. Initial characterization of Samba has revealed some structural information, although the preparation techniques used are prone to the generation of structural artifacts. To generate more native-like structural information for Samba, we analyzed the virus through cryo-electron microscopy, cryo-electron tomography, scanning electron microscopy, and fluorescence microscopy. These microscopy techniques demonstrated that Samba particles have a capsid diameter of ~527 nm and a fiber length of ~155 nm, making Samba the largest Mimivirus yet characterized. We also compared Samba to a fiberless mimivirus variant. Samba particles, unlike those of mimivirus, do not appear to be rigid, and quasi-icosahedral, although the two viruses share many common features, including a multi-layered capsid and an asymmetric nucleocapsid, which may be common amongst the Mimiviruses.

Concepts: Electron microscope, Virology, Organism, Brazil, Microscope, Electron, Genome, Virus


Myxoma virus (MYXV) is the type species of the Leporipoxviruses, a genus of Chordopoxvirinae, double stranded DNA viruses, whose members infect leporids and squirrels, inducing cutaneous fibromas from which virus is mechanically transmitted by biting arthropods. However, in the European rabbit (Oryctolagus cuniculus), MYXV causes the lethal disease myxomatosis. The release of MYXV as a biological control for the wild European rabbit population in Australia, initiated one of the great experiments in evolution. The subsequent coevolution of MYXV and rabbits is a classic example of natural selection acting on virulence as a pathogen adapts to a novel host species. Slightly attenuated mutants of the progenitor virus were more readily transmitted by the mosquito vector because the infected rabbit survived longer, while highly attenuated viruses could be controlled by the rabbit immune response. As a consequence, moderately attenuated viruses came to dominate. This evolution of the virus was accompanied by selection for genetic resistance in the wild rabbit population, which may have created an ongoing co-evolutionary dynamic between resistance and virulence for efficient transmission. This natural experiment was repeated on a continental scale with the release of a separate strain of MYXV in France and its subsequent spread throughout Europe. The selection of attenuated strains of virus and resistant rabbits mirrored the experience in Australia in a very different environment, albeit with somewhat different rates. Genome sequencing of the progenitor virus and the early radiation, as well as those from the 1990s in Australia and Europe, has shown that although MYXV evolved at high rates there was no conserved route to attenuation or back to virulence. In contrast, it seems that these relatively large viral genomes have the flexibility for multiple pathways that converge on a similar phenotype.

Concepts: Genetics, Genome, Virus, European Rabbit, Rabbit, Gene, Evolution, DNA


The English sweating sickness caused five devastating epidemics between 1485 and 1551, England was hit hardest, but on one occasion also mainland Europe, with mortality rates between 30% and 50%. The Picardy sweat emerged about 150 years after the English sweat disappeared, in 1718, in France. It caused 196 localized outbreaks and apparently in its turn disappeared in 1861. Both diseases have been the subject of numerous attempts to define their origin, but so far all efforts were in vain. Although both diseases occurred in different time frames and were geographically not overlapping, a common denominator could be what we know today as hantavirus infections. This review aims to shed light on the characteristics of both diseases from contemporary as well as current knowledge and suggests hantavirus infection as the most likely cause for the English sweating sickness as well as for the Picardy sweat.

Concepts: Infectious disease, Hantavirus


Influenza A viruses (IAVs) cause seasonal pandemics and epidemics with high morbidity and mortality, which calls for effective anti-IAV agents. The glycoprotein hemagglutinin of influenza virus plays a crucial role in the initial stage of virus infection, making it a potential target for anti-influenza therapeutics development. Here we found that quercetin inhibited influenza infection with a wide spectrum of strains, including A/Puerto Rico/8/34 (H1N1), A/FM-1/47/1 (H1N1), and A/Aichi/2/68 (H3N2) with half maximal inhibitory concentration (IC50) of 7.756 ± 1.097, 6.225 ± 0.467, and 2.738 ± 1.931 μg/mL, respectively. Mechanism studies identified that quercetin showed interaction with the HA2 subunit. Moreover, quercetin could inhibit the entry of the H5N1 virus using the pseudovirus-based drug screening system. This study indicates that quercetin showing inhibitory activity in the early stage of influenza infection provides a future therapeutic option to develop effective, safe and affordable natural products for the treatment and prophylaxis of IAV infections.

Concepts: Pandemic, Antiviral drug, Avian influenza, Transmission and infection of H5N1, 2009 flu pandemic, Influenza pandemic, Virus, Influenza


In contrast to previous incursions of highly pathogenic avian influenza (HPAIV) H5 viruses, H5N8 clade viruses caused numerous cases of lethal infections in white-tailed sea eagles (Haliaeetus albicilla) affecting mainly young eagles (younger than five years of age) in Germany during winter 2016/2017. Until April 2017, 17 HPAIV H5N8-positive white-tailed sea eagles had been detected (three found alive and 14 carcasses) by real-time RT-PCR and partial nucleotide sequence analyses. Severe neurological clinical signs were noticed which were corroborated by immunohistopathology revealing mild to moderate, oligo- to multifocal necrotizing virus-induced polioencephalitis. Lethal lead (Pb) concentrations, a main factor of mortality in sea eagles in previous years, could be ruled out by atomic absorption spectrometry. HPAIV H5 clade reportedly is the first highly pathogenic influenza virus known to induce fatal disease in European white-tailed see eagles. This virus strain may become a new health threat to a highly protected species across its distribution range in Eurasia. Positive cloacal swabs suggest that eagles can spread the virus with their faeces.


Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and “blinding” the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.

Concepts: Bacteria, Antibody, Protein, Measles, Squamous cell carcinoma, Vaccine, Cancer, Immune system


The transmission cycle of chikungunya virus (CHIKV) requires that mosquito vectors get persistently infected with the virus, following its oral acqsuisition from a vertebrate host. The mosquito midgut is the initial organ that gets infected with orally acquired CHIKV. Following its replication in the midgut epithelium, the virus exits the midgut and infects secondary tissues including the salivary glands before being transmitted to another host. Here, we investigate the pattern of CHIKV dissemination from the midgut of Aedes aegypti at the ultrastructural level. Bloodmeal ingestion caused overstretching of the midgut basal lamina (BL), which was disrupted in areas adjacent to muscles surrounding the midgut as shown by scanning electron microscopy (SEM). Using both transmission electron microscopy (TEM) and focused ion beam scanning electron microscopy (FIB-SEM) to analyze midgut preparations, mature chikungunya (CHIK) virions were found accumulating at the BL and within strands of the BL at 24⁻32 h post-infectious bloodmeal (pibm). From 48 h pibm onwards, virions no longer congregated at the BL and became dispersed throughout the basal labyrinth of the epithelial cells. Ingestion of a subsequent, non-infectious bloodmeal caused mature virions to congregate again at the midgut BL. Our study suggests that CHIKV needs a single replication cycle in the midgut epithelium before mature virions directly traverse the midgut BL during a relatively narrow time window, within 48 h pibm.


Dromedary camels (Camelus dromedarius) are now known to be the vertebrate animal reservoir that intermittently transmits the Middle East respiratory syndrome coronavirus (MERS-CoV) to humans. Yet, details as to the specific mechanism(s) of zoonotic transmission from dromedaries to humans remain unclear. The aim of this study was to describe direct and indirect contact with dromedaries among all cases, and then separately for primary, non-primary, and unclassified cases of laboratory-confirmed MERS-CoV reported to the World Health Organization (WHO) between 1 January 2015 and 13 April 2018. We present any reported dromedary contact: direct, indirect, and type of indirect contact. Of all 1125 laboratory-confirmed MERS-CoV cases reported to WHO during the time period, there were 348 (30.9%) primary cases, 455 (40.4%) non-primary cases, and 322 (28.6%) unclassified cases. Among primary cases, 191 (54.9%) reported contact with dromedaries: 164 (47.1%) reported direct contact, 155 (44.5%) reported indirect contact. Five (1.1%) non-primary cases also reported contact with dromedaries. Overall, unpasteurized milk was the most frequent type of dromedary product consumed. Among cases for whom exposure was systematically collected and reported to WHO, contact with dromedaries or dromedary products has played an important role in zoonotic transmission.