virology blog
About viruses and viral disease
TWiV reviews the emergence of remdesivir-resistant SARS-CoV-2 during treatment of a persistently infected immunocompromised patient, and how altered TMPRSS2 utilization by the Omicron variant influences infectivity and fusion.
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The TWiVers discuss the spread of African swine fever virus and its threat to pig farming, and the zoonotic potential of peste des petits ruminants virus.
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The protein syncytin, which is essential for formation of the placenta, originally came to the genome of our ancestors, and those of other mammals, via a retrovirus infection. Placental structures have also developed in non-mammalian vertebrates. The Mabuya lizard (pictured: image credit), which emerged 25 million years ago, has a placenta very much like those in mammals, and its development was likely driven by capture of a retroviral gene.
[Read more…] about Retroviruses turned egg-layers into live-bearers
The entry of enveloped viruses into cells begins when the membrane that surrounds these virus particles fuse with a cell membrane. The process of virus-cell fusion must be tightly regulated, to make sure it happens in the right cells. The fusion activity of measles viruses isolated from the brains of AIDS patients is not properly regulated, which might explain why these viruses cause disease in the central nervous system.
Measles virus particles bind to cell surface receptors via the viral glycoprotein HN (illustrated). Once the viral and cell membranes have been brought together by this receptor-ligand interaction, fusion is induced by a second viral glycoprotein called F, and the viral RNA is released into the cell cytoplasm. The N-terminal 20 amino acids of F protein are highly hydrophobic and form a region called the fusion peptide that inserts into target membranes to initiate fusion. Because F-protein-mediated fusion can occur at neutral pH, it must be controlled, to ensure that virus particles fuse with only the appropriate cell, and to prevent aggregation of newly made virions. The fusion peptide of F is normally hidden, and conformational changes in the protein thrust the it toward the cell membrane (illustrated). These conformational changes in the F protein, which expose the fusion peptide, are thought to occur upon binding of HN protein to its cellular receptor.
During a recent outbreak of measles in South Africa, several AIDS patients died when measles virus entered and replicated in their central nervous systems. Measles virus normally enters via the respiratory route, establishes a viremia (and the characteristic rash) and is cleared within two weeks. The virus is known to enter the brain in up to half of infected patients, but without serious sequelae. The measles inclusion body encephalitis observed in these AIDS patients typically occurs in immunosuppressed individuals several months after infection with measles virus.
Measles virus isolated postmortem from these two individuals had a single amino acid change in the F glycoprotein, from leucine to tryptophan at position 454. This single amino acid change allowed viruses to fuse with cell membranes without having to first bind a cellular receptor via the HN glycoprotein. In other words, the normal mechanism for regulating measles virus fusion – binding a cell receptor – was bypassed in these viruses. This unusual property might have allowed measles virus to spread throughout the central nervous system, causing lethal disease.
How did these mutant viruses arise in the AIDS patients? Because these individuals had impaired immunity as a result of HIV-1 infection, they were not able to clear the virus in the usual two weeks. As a consequence, the virus replicated for several months. During this time, the mutation might have arisen that allowed unregulated fusion of virus and cell, leading to unchecked replication in the brain. Alternatively, the mutation might have been present in virus that infected these individuals, and was selected in the central nervous system.
An interesting question is whether these neurotropic measles viruses can be transmitted by aerosol between hosts – a rather unsettling scenario. Fortunately, we do have a measles virus vaccine that effectively prevents infection, even with these mutant viruses.
On this episode of the science show This Week in Virology, which was recorded before a large enthusiastic audience at the annual meeting of the American Society for Virology, Vincent, Rich, and Kathy speak with Rebecca and Christiane about their work on metapneumoviruses and noroviruses.
You can find TWiV #243 at www.microbe.tv/twiv.
Broad spectrum antibiotics are available that act against a wide range of bacteria, including both gram-positive and gram-negative species. In contrast, our antiviral arsenal is exceedingly specific. Nearly all the known antivirals block infection with one or two different viruses. The discovery of a compound that blocks infection with many different enveloped viruses may change the landscape of antiviral therapy.
A small molecule has been discovered that inhibits infection by a wide range of viruses with membranes, the so-called enveloped viruses. The compound, called LJ001, is a derivative of aryl methylene rhodanine. It was discovered in a search for compounds that block the entry of Nipah virus into cells. LJ001 was then found to block infection of cells by a wide variety of enveloped viruses, including filoviruses (Ebola, Marburg); influenza A virus; arenaviruses (Junin), bunyaviruses (Rift Valley fever virus, LaCrosse virus); flaviviruses (Omsk hemorrhagic fever virus, Russian spring-summer encephalitis virus, yellow fever virus, hepatitis C virus, West Nile virus); paramyxoviruses (Nipah virus, parainfluenza virus, Newcastle disease virus); retroviruses (HIV-1, murine leukemia virus); rhabdoviruses (vesicular stomatitis virus); and poxviruses (cowpox virus, vaccinia virus). The compound had no effect on viruses without an membrane, such as adenovirus, coxsackievirus, and reovirus.
To determine which step of viral infection is blocked, LJ001 was added at different times during infection. Inhibition of infection was observed when LJ001 and virus were incubated before being added to the cell. However, if the virus was allowed to enter the cell, addition of the compound had no effect on the production of infectious virus. Inclusion of LJ001 into the culture medium did prevent virus spread to neighboring cells.
LJ001 inhibits such a wide spectrum of viruses because it targets a feature common to all of them: the viral envelope (see image of influenza virus for an example). The compound blocks virus infection by inserting into the viral membrane and inhibiting entry into the cell. It does not block virus attachment to cells, but impairs fusion of the viral and cell membranes, a step essential for entry of the viral genome into cells. However, LJ001 is not toxic to cells, and does not inhibit the fusion of neighboring cells caused by some viral infections.
How might LJ001 impair viral but not cellular membranes? One explanation is that the compound damages both viral and cell membranes. The latter can be repaired and consequently escape the toxic effects of the drug. In contrast, viral membranes are static, and once damaged by LJ001 they can no longer function properly during virus entry into cells.
Whether LJ001 and derivatives will be useful for treating virus infections in animals awaits the results of testing in animal models and then in humans. Meanwhile, an interesting question is whether viral mutants resistant to LJ001 and its derivatives will emerge. Just because the drug targets a component derived from the host cell does not mean that resistance will not emerge. The drug brefeldin A, an inhibitor of poliovirus, blocks a cellular enzyme, yet viral mutants resistant to the drug have been identified. One possibility for the mechanism of resistance could be amino acid changes in viral glycoproteins that protect the viral membrane from damage caused by LJ001.
Perhaps it’s not a matter of whether mutants resistant to LJ001 will emerge, but when they will be identified.
Wolf, M., Freiberg, A., Zhang, T., Akyol-Ataman, Z., Grock, A., Hong, P., Li, J., Watson, N., Fang, A., Aguilar, H., Porotto, M., Honko, A., Damoiseaux, R., Miller, J., Woodson, S., Chantasirivisal, S., Fontanes, V., Negrete, O., Krogstad, P., Dasgupta, A., Moscona, A., Hensley, L., Whelan, S., Faull, K., Holbrook, M., Jung, M., & Lee, B. (2010). A broad-spectrum antiviral targeting entry of enveloped viruses Proceedings of the National Academy of Sciences, 107 (7), 3157-3162 DOI: 10.1073/pnas.0909587107