TWiV 431: Niemann-Pick of the weak

The TWiVirions reveal bacteriophage genes that control eukaryotic reproduction, and the biochemical basis for increased Ebolavirus glycoprotein activity during the recent outbreak.

You can find TWiV #431 at microbe.tv/twiv, or listen below.

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TWiV Special: Vincent Munster on MERS-coronavirus and Ebolavirus

At the Rocky Mountain Laboratory in Hamilton, Montana, Vincent speaks with Vincent Munster about the work of his laboratory on MERS-coronavirus and Ebolaviruses.

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Building an Ebola Virus Lab in Sierra Leone with Ian Goodfellow

I spoke with virologist Ian Goodfellow, whose laboratory works on noroviruses, about why he went to Sierra Leone to establish an Ebolavirus diagnostic and sequencing laboratory. The obstacles he encountered were considerable, but the results were very useful. Recorded at the Emerging Infectious Diseases A to Z (EIDA2Z) conference hosted by the National Emerging Infectious Diseases Laboratories (NEIDL).

TWiV 422: Watching the icosahedron drop

The TWiVestigators wrap up 2016 with a discussion of the year’s ten compelling virology stories.

You can find TWiV #422 at microbe.tv/twiv, or listen below.

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TWiV 394: Cards in a hand

Vincent and Alan speak with Erica Ollmann Saphire about her career and her work on understanding the functions of proteins of Ebolaviruses, Marburg virus, and other hemorrhagic fever viruses, at ASM Microbe 2016 in Boston, MA.

You can find TWiV #394 at microbe.tv/twiv, or listen or watch the video below.

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TWiV 381: Add viruses and Zimmer

TWiVOn episode #381 of the science show This Week in Virology, Carl Zimmer joins the TWiV team to talk about his career in science writing, the real meaning of copy-paste, science publishing, the value of Twitter, preprint servers, his thoughts on science outreach, and much more.

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A promising Ebolavirus antiviral compound

ATP EBOV antiviralA small molecule antiviral compound has been shown to protect rhesus monkeys against lethal Ebolavirus disease, even when given up to three days after virus inoculation.

The compound, called GS-5734, is a nucleoside analog. After uptake into cells, GS-5734 is converted to a nucleoside triphosphate (illustrated, bottom panel) which is incorporated by the viral RNA dependent RNA polymerase as it copies the viral genome. However, the nucleoside is chemically different from ATP (illustrated, top) and no further nucleotides can be incorporated into the growing RNA strand. RNA synthesis ceases, blocking production of infectious virus particles.

In cell culture GS-5734 inhibits viral replication at micromolar concentrations, in a variety of human cell types including monocyte-derived macrophages, primary macrophages, endothelial cells, and a liver cell line. The drug inhibits replication of several strains of Zaire ebolavirus, including Kikwit and Makona (from the West African outbreak); Bundibugyo ebolavirus, and Sudan ebolavirus. It also inhibits replication of another filovirus, Marburg virus, as well as viruses of different families, including respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-coronavirus, but not chikungunya virus, Venezuelan equine encephalitis virus, or HIV-1.

The RNA dependent RNA polymerase of Ebolaviruses has not yet been produced in active form, so the authors determined whether GS-5734 inhibits a related polymerase from respiratory syncytial virus. As predicted, the compound was incorporated into growing RNA chains by the enzyme, and caused premature termination.

Typically tests of antiviral candidates begin in a small animal, and if the results are promising, proceed to nonhuman primates. While a mouse model of Ebolavirus infection is available, the serum from these animals degrades GS-5374. Consequently a rhesus monkey model of infection was used to test the compound.

After intravenous administration of GS-5374, the NTP derived from it was detected in peripheral blood mononuclear cells, testes, epididymis, eyes, and brain within 4 hours. All 12 monkeys inoculated intramuscularly with Zaire ebolavirus died by 9 days post-infection. In contrast, all animals survived after administration of GS-5374 2 or 3 days after virus inoculation. These animals also had reduced virus associated pathology as measured by liver enzymes in the blood and blod clotting. Viral RNA in serum reaches 109 copies per milliliter on days 5 and 7 in untreated animals, and was undetectable in 4 of 6 treated animals.

It is likely that resistant viruses can be obtained by passage in the presence of GS-5734; whether such mutant viruses emerge early in infection, and at high frequency, is an important question that will impact clinical efficacy of the drug. The authors did not detect changes in the viral RNA polymerase gene that might be assoicated with resistance, but further work is needed to address how readily such mutants arise.

These promising results have lead to the initiation of a phase I clinical trial to determine whether GS-5734 is safe to administer to humans, and if the drug reaches sites where Ebolaviruses are known to replicate. However, determining the efficacy of the compound requires treatment of acutely Ebolavirus infected humans, of which there are none. It might be of interest to determine the ability of GS-5734 to clear persistent virus from previously infected individuals.

You can bet that GS-5734 has already been tested for activity against Zika virus.

TWiEVO 5: Looking at straw colored fruit bats through a straw

TWiEVOOn episode #5 of the science show This Week in Evolution, Sara Sawyer and Kartik Chandran join Nels and Vincent to talk about how the filovirus receptor NPC1 regulates Ebolavirus susceptibility in bats.

You can find TWiEVO #5 at microbe.tv/twievo, or you can listen below.

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Zika from sex, the byway but not the highway

FlavivirusCan Zika virus be sexually transmitted? Perhaps in very rare cases, but the main mode of transmission is certainly via mosquitoes. That’s why I’ve shamelessly stolen a quote on this topic from Dr. William Schaffner of Vanderbilt University:

Mosquito transmission is the highway, whereas sexual transmission is the byway. Sexual transmission cannot account for this sudden and widespread transmission of this virus.

If you just read the news headlines, which many people do, you will think that Zika virus spreads like HIV. But it does not.

Let’s make a clear distinction between sexually transmitted viruses (like HIV – sex is the main mode of transmission, along with contaminated blood), versus sexually transmissible viruses. The latter includes viruses that now and then might be sexually transmitted under certain circumstances, but which normally are transmitted by another route. Zika virus is transmitted among humans by mosquitoes. If sexual transmission occurs, it is very, very rare, given the large number of Zika virus infections that have been documented.

Is Zika virus sexually transmissible?

The first hint of sexual transmission of Zika virus came from the story of two American scientists working in Senegal in 2008, where they were sampling mosquitoes. Between 6-9 days after returning to their homes in Colorado, they developed a variety of symptoms of infection including fatigue, headache, chills, arthralgia, and a maculopapular rash. The wife of one patient had not traveled to Africa, yet she developed similar symptoms three days after her husband. Analysis of paired acute and convalescent sera from all three patients revealed antibodies against Zika virus. The authors of the study do not conclude that transmission from husband to wife was via sexual activity – they suggest it as a possiblity. Their data could not prove sexual transmission.

More recently infectious Zika virus was detected in semen of a French Polynesian male who had recovered from infection. The presence of virus in semen is compatible with sexual transmission, but the patient was not known to have transmitted infection to anyone.

The CDC has concluded that Zika virus was transmitted to an individual in Texas who had sex with a traveler returning from Venezuela. As of this writing I do not know exactly how the CDC came to this conclusion.

What would be needed to prove that Zika virus is sexually transmissible?

Polymerase chain reaction (PCR) is used to diagnose many viral diseases. This assay detects small fragments of viral nucleic acid and can be very specific. However as we are trying to establish for the first time that Zika virus can be transmitted sexually, more than PCR must be done – infectious virus should be recovered from the donor and recipient. A positive PCR result does not mean that infectious virus is present in the sample, only fragments of the genome, which of course would not be infectious. It is important to correlate the presence of infectious virus with sexual transmission.

Not only should infectious virus be recovered from both donor and recipient, but the viral genome sequences should be nearly identical, providing strong evidence for sexual transmission. If the viral genome sequences were substantially different, this result could imply that the infection was acquired from someone else.

Looking for anti-viral antibodies in serum is a good way to confirm virus infection when virus is no longer present. However it is not as specific as PCR or virus isolation, and does not provide information about the genome of the donor and recipient virus.

Sexual transmission of Ebolavirus still remains speculative. There are several suspected cases, and many examples of PCR positive semen samples from men who have recovered from the disease. It’s not easy to prove that a virus can be transmitted sexually, especially when it is a rare event.

Just as we are not sure that Zika virus causes microencephaly, we are not sure if it can be sexually transmitted.

TWiV 370: Ten out of 15

On episode #370 of the science show This Week in Virology, the TWiVomics review ten captivating virology stories from 2015.

You can find TWiV #370 at www.microbe.tv/twiv.