The membranes of enveloped viruses contain embedded proteins that are essential for attaching to cell receptors and fusing with cell membranes. We generally view these glycoproteins as evenly distributed over the surface of the virus particle, as illustrated for influenza virus. But many more envelope glycoproteins are involved in attachment and entry of larger viruses, and at least for vaccinia virus, they appear to be spatially polarized on virus particles.

The genome of vaccinia virus encodes 4 proteins for binding to cells, and 11 proteins for fusion. The latter form the entry fusion complex or EFC. A clue that these proteins are not evenly distributed came from the results of electron microscopy studies, which revealed that the sides of virus particles bind to cells, while fusion occurs at the tips.

Super-resolution microscopy and single particle analysis were used to show that the vaccinia virus binding proteins are located on the sides of virus particles, while EFC proteins are at the tips. This polarized pattern is diagrammed in the figure below (WT).

polarized vaccinia virus

Vaccinia virus membrane protein organization in wild type and mutant viruses. Purple proteins are involved in fusion; others in binding. Image credit.

Removal of single genes encoding EFC components, such as G9 or O3, led to loss of this polarized structure (right panel in figure). These viral mutants are defective for fusion, suggesting a role for polarization in this virus entry.

Another viral protein, A27, is not a component of the EFC but is essential for fusion. Viruses lacking the A27 gene also display non-polarized glycoproteins, as shown in the figure below.

vaccinia virus A27 mutant

Vaccinia virus membrane protein organization in WT and A27 mutant. Image credit

Although the A27 protein is not a transmembrane protein – it is attached to the virus surface via interactions with the A17 protein (see illustration above) – it nevertheless is required for polarized clustering of the EFC at the tips of virus particles.

The authors believe that the clustering of the vaccinia virus EFC is essential for efficient virus-cell fusion. What is the function of having fusion proteins localized to the tips of the virus particles? The authors suggest that concentrating the fusion proteins at the virus tips increases the chances of successful infection.  Why this is not the case for most other viruses is a good question – or maybe it has simply not been examined.

By David Tuller, DrPH

Not long ago, Sir Simon scored an own goal by enticing a childhood buddy to enter the PACE debate. That buddy, attorney and social commentator Mike Godwin, soon pronounced the trial—which Sir Simon had called “a thing of beauty”–to be “so profoundly flawed that it cannot be trusted.” Sir Simon tweeted out a brave front in the face of his friend’s rejection of PACE, reaffirming his own belief that the trial was well-conducted. Whatever. Godwin agreed to sign the open letter to Lancet editor Richard Horton.

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By David Tuller, DrPH

Two months ago, Professor Racaniello sent Lancet editor Richard Horton an open letter about the indisputable methodological and ethical failings of the PACE trial. This was a follow-up to Virology Blog’s 2016 open letter to Dr. Horton; the new one detailed what has happened since then. Last month, I re-sent and reposted this new open letter, with organizations also signed on. Given Dr Horton’s persistent defense of a study in which 13 % of the participants had already met a key outcome threshold at baseline, it is not surprising that he has failed to respond.

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The TWiVniks explain how the three-dimensional structure of the giant Cafeteria roenbergensis virus suggests a new mode of assembly, and the apparent elimination of dengue fever in an Australian city by release of mosquitoes harboring Wolbachia.

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C. destructans life cycle

Proposed C. destructans life cycle. Host mitchondria is brown. Image credit.

What do you call a small bacterium that acts like a virus, infecting and lysing eukaryotic cells? Chromulinavvorax destructans, of course!

As part of a study to identify pathogens that infect protist zooplankton, particles smaller than 0.8 microns were obtained from freshwater habitats in southwestern British Columbia, and used to infect cultures of protists.

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By David Tuller, DrPH

Last week I admonished the US Centers for Disease Control for including fuzzy language about exercise in its new package of “information for healthcare providers.” The way the Mayo Clinic deals with the illness it calls chronic fatigue syndrome is an excellent illustration of why it is so important for the CDC to stop fudging and get this right.

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TWiV 505: Rosebola

The TWiV hosts review persistence of Ebola virus after the end of the Liberian outbreak, and the potential role of two herpesviruses in the pathogenesis of Alzheimer’s disease.

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Roseola on 21 month old

Roseola. Image credit.

Risk factors for the chronic neurodegenerative condition known as Alzheimer’s disease (AD) include many cellular genes and pathogenic microbes. Nucleic acids of two ubiquitous human herpesviruses, HHV-6A and HHV-7, have been found at higher levels in AD brains compared with healthy controls, and appear to regulate genes implicated in risk of developing the disease.

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By David Tuller, DrPH

Last summer, the US Centers for Disease Control removed graded exercise therapy and cognitive behavior therapy from its website as recommendations for treatment of the illness it was by then calling ME/CFS. Its stated explanation for the change–that readers had misunderstood the recommendations–was nonsense. Readers understood all too well what the agency meant by GET and CBT. The CDC’s related claim—that these were just generic disease management strategies and had nothing at all to do with PACE—was equally ridiculous. (The agency had previously removed references to the PACE trial while leaving the CBT/GET recommendations in place.)

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The TWiVerinos discuss Nipah virus and the recent outbreak in India, and the first cast of polio in Papua New Guinea in 18 years.

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