On episode #299 of the science show This Week in VirologyVincent visits the Rocky Mountain Laboratories in Hamilton, Montana and speaks with Marshall Bloom, Sonja Best, and Byron Caughey about their work on tick-born flaviviruses, innate immunity, and prion diseases.

You can find TWiV #299 at www.twiv.tv.

Many people have a new awareness of the disease known as amyotrophic lateral sclerosis, or ALS, thanks to the Ice Bucket Challenge initiated by the ALS Association. Fewer might know that retroviruses have been proposed to play a role in the development of the disease.

I previously summarized a 2008 paper on ALS in a piece called Retroviruses and amyotrophic lateral sclerosisSera from some ALS patients had previously been shown to contain elevated levels of reverse transcriptase, an enzyme found in retrovirus particles. In the 2008 paper, RNAs encoding this enzyme were reported in the brains of ALS patients, and their origin appears to be the human endogenous retrovirus HERV-K.

The progress made in understanding the relationship of endogenous retroviruses with ALS is summarized in a review published in August of 2014 entitled Retroviruses and amyotrophic lateral sclerosis (the paper is open access). The authors conclude:

A comprehensive study of the expression or reactivation of endogenous retroviral elements in ALS has not yet been undertaken. The literature on HERV-W involvement in ALS is difficult to interpret. Two independent reports, however, have shown increased HERV-K expression in both serum and brain tissue in ALS patients. It remains unknown if HERV-K expression is an epiphenomenon or plays a pathophysiological role in the disease.

I am pleased to participate in the Ice Bucket Challenge to help raise awareness of ALS and raise money to work on the disease.

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TWiV 298: MV-NIS de myelo

17 August 2014

On episode #298 of the science show This Week in Virology, the TWiV gang answers follow-up questions about the Ebola virus outbreak in West Africa, then discuss treatment of  disseminated multiple myeloma with oncolytic measles virus.

You can find TWiV #298 at www.twiv.tv.

TWiV 300This Week in Virology, the podcast about viruses – the kind that may or may not make you sick, celebrates its 300th episode on Tuesday, August 26, 2014 with a live recording at the Washington, DC headquarters of the American Society for Microbiology. This special episode will be part of the ‘Microbes after Hours’ series, and will feature the TWiV hosts Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Kathy Spindler recording together in person for the first time.

TWiV 300 will be live-streamed, but if you live in the Washington, DC area, you are welcome to join us and watch the episode in person. We have a limited number of seats available on a first come, first serve basis. Click the RSVP link below to register.

Date: Tuesday, August 26, 2014

Reception from 6-7 PM at ASM Headquarters, 1752 N Street, N.W. Washington, D.C. 20036-2904

TWiV 300th Episode live from 7-8 PM RSVP required to attend.

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On episode #297 of the science show This Week in Virology, the TWiVites present an all-ebolavirus episode, tackling virology, epidemiology, and approaches to prevention and cure that are in the pipeline.

You can find TWiV #297 at www.twiv.tv.

guinea-liberia-sierra-leone-2014As the epidemic of Zaire ebolavirus in Western Africa continues (1,779 cases and 961 deaths in four countries), many are questioning why there are no means of preventing or stopping infection. In the past two decades there has been substantial research into developing and testing active and passive vaccines and antiviral drugs, although none have yet been licensed for use in humans.

Using antibodies to treat infection with ebolaviruses with antibodies is probably the best known therapy, because it was used to treat a two Americans who were infected while working in Liberia. They received a mixture of three monoclonal antibodies (called ZMapp) which had been previously shown to block infection of cells with ebolaviruses, and prevent lethal infection of non-human primates when given within 24-48 hours after infection. These are mouse monoclonal antibodies that have been ‘humanized’ so that when given to people they do not induce an antibody response against the antibodies. Humanization involves changing the amino acids of the antibody molecule from mouse to human, except in the part of the antibody that binds antigen. The antibodies are then synthesized in tobacco plants and purified. Administering anti-viral antibodies to patients, also called passive immunization, was done long before vaccines were available. Serum from patients who had recovered from a particular disease would be given to others who had recently been infected, in order to prevent disease. Such therapy was used to save the life of virologist Jordi Casals, who had become infected with Lassa virus while isolating the virus from the blood of a patient, Penny Pinneo. The serum administered to Casals was obtained from Pinneo, who had recovered from the infection. The American doctor infected with Zaire ebolavirus while working in Liberia was also given serum from a boy who had recovered from infection.

As ZMapp has not yet been subjected to human clinical trials to determine its safety and efficacy, its use in an infected human is considered unusual. A phase I clinical trial needs to be done to ensure that the preparation of monoclonal antibodies is safe in humans. Determining whether monoclonal antibody therapy for ebolavirus infection is effective is more difficult. Such testing could only be done during an outbreak, during which it would not be ethical to withhold treatment from the control group. Nevertheless it is clear that such mixtures of monoclonal anti-viral antibodies could potentially save many lives during outbreaks.

While passive immunization has value in saving lives, its protection is temporary: the antibodies given to patients do not endure. A better approach is immunization, which not only induces anti-viral antibodies, but creates immune memory, so that subsequent infections are accompanied by another round of antibody production. The catch is that it takes about two weeks after immunization for antibodies to reach sufficient protective levels. Nevertheless, a vaccine would likely have had substantial impact on the current outbreak, which began in March 2014 and has continued for 5 months.

A number of experimental vaccines against ebolaviruses are in development. In one approach, the glycoprotein of vesicular stomatitis virus is replaced with the corresponding protein of different ebolaviruses. These vaccines protect non-human primates from lethal infection. A similar approach using an attenuated rabies virus to deliver the ebolavirus glycoprotein also protected non-human primates from infection, as did immunization with an adenovirus encoding the ebolavirus glycoprotein.  This vaccine candidate has been shown to be safe and immunogenic in phase I clinical trials. Another vaccine approach entails production of the ebolavirus glycoprotein in E. coli. Immunization of mice with the purified protein leads to the production of neutralizing antibodies. Because protein-based vaccines do not replicate, the immune response may need to be boosted by using an adjuvant that stimulates the innate immune system and leads to better antibody production. A double-stranded RNA adjuvant has been shown to augment the immune response against a non-infections, virus-like particle vaccine containing the Ebola virus glycoprotein but not the viral genome.

Antivirals certainly have a place in control of viral disease, and a number of promising candidates to control infection with ebolaviruses have been developed. One is a nucleoside analog which is incorporated into RNA by the viral RNA polymerase and leads to chain termination. It blocks replication of ebolaviruses in culture cells, and protects mice and nonhuman primates from lethal infection. This compound, called BCX4430, is a broad spectrum antiviral that inhibits the replication of not only members of the Filoviridae, but also Arenaviridae, Bunyaviridae, Orthomyxoviridae, Picornaviridae, Paramyxoviridae, Flaviviridae, Coronaviridae. Another inhibitor of viral RNA synthesis is favipiravir, which has the advantage of being in late stage clinical development for the treatment of influenza. This compound inhibits replication of ebolaviruses in cultured cells and reduces disease severity and mortality in a mouse model of disease.

It is likely that the extent of the current outbreak of Ebola virus disease, the largest to date, will provide impetus to move some of these treatments into human trials. But consider that all the research on active and passive vaccines and antivirals for ebolaviruses required work in BSL-4 laboratories. Those who call for the shuttering of BSl-4 laboratories need to take note and move away from their unrealistic and unreasonable position.

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Dr. Tom Solomon is Director of the Institute for Infection and Global Health at the University of Liverpool. Here he speaks with Vincent Racaniello about the 2014 outbreak of Zaire ebolavirus in West Africa. Dr. Solomon discusses why the epidemic has spread, how it might be curtailed, the return of two infected health workers back to the United States for treatment, and the possibility that he might be traveling to the affected region to assist with medical care.

 
 

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On episode #296 of the science show This Week in Virology, Vincent visits the Australian Animal Health Laboratory in Geelong, Australia and speaks with Linfa about his work on bats and bat viruses.

You can find TWiV #296 at www.twiv.tv.

After recording this episode, Vincent and Linfa drove to a nearby golf course where they watched a colony of bats awaken and fly into the night. Below is a video of that experience.

Scientists for Science

28 July 2014

Scientists for Science are confident that biomedical research on potentially dangerous pathogens can be performed safely and is essential for a comprehensive understanding of microbial disease pathogenesis, prevention and treatment. The results of such research are often unanticipated and accrue over time; therefore, risk-benefit analyses are difficult to assess accurately.

If we expect to continue to improve our understanding of how microorganisms cause disease we cannot avoid working with potentially dangerous pathogens. In recognition of this need, significant resources have been invested globally to build and operate BSL-3 and BSL-4 facilities, and to mitigate risk in a variety of ways, involving regulatory requirements, facility engineering and training. Ensuring that these facilities operate safely and are staffed effectively so that risk is minimized is our most important line of defense, as opposed to limiting the types of experiments that are done.

In contrast to recombinant DNA research at the time of Asilomar in 1975, studies on dangerous pathogens are already subject to extensive regulations. In addition to regulations associated with Select Agent research, experimental plans on other pathogens are peer reviewed by scientists and funding agencies, and the associated risk assessments are considered by biosafety experts and safety committees. Risk mitigation plans are proposed and then considered and either approved or improved by safety committees.

If there is going to be further discussion about these issues, we must have input from outside experts with the background and skills to conduct actual risk assessments based on specific experiments and existing laboratories. Such conversations are best facilitated under the auspices of a neutral party, such as the International Union of Microbiological Societies or the American Society for Microbiology, or national academies, such as the National Academy of Sciences, USA. We suggest they should organize a meeting to discuss these issues.

Scientists for Science have a range of opinions on how risk is best assessed. However, maintaining dogmatic positions serves no good purpose; only by engaging in open constructive debate can we learn from one another’s experience. Most importantly, we are united as experts committed to ensuring public health is not compromised and the reputation of science in general, and microbiology in particular, is defended.

Please visit the Scientists for Science website to view the supporters of this initiative.

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On episode #293 of the science show This Week in VirologyVincent visits Melbourne, Australia and speaks with Melissa, Alex, Gilda, and Paul about their work on HIV infection of the central nervous system, West Nile virus, microbicides for HIV, and the Koala retrovirus.

You can find TWiV #293 at www.twiv.tv.