virology blog

About viruses and viral disease

Vincent Racaniello

Defective genomes modulate respiratory syncytial virus pathogenesis

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During viral replication, defective genomes may arise that lack essential sequences. These so-called defective genomes cannot replicate unless they are in the same cell as a helper virus. Defective genomes play a role in modulating pathogenesis of respiratory syncytial virus in humans.

Copy-back defective viral genomes (cbDVGs) of RSV arise when the viral RNA polymerase halts and then turns around and begins copying the nascent strand (illustrated below – image credit). Because the cbDVGs have strands of both (+) and (-) polarity it is possible to design primers to amplify them by RT-PCR.

It has been suspected that defective viral genomes might modulate viral pathogenesis because they are efficient inducers of interferon. In a study of 122 hospitalized pediatric patients with RSV infection, the presence of cbDVGs was associated with higher viral loads and longer hospitalizations. Furthermore, patients harboring cbDVGs had higher expression of pro-inflammatory cytokine genes.

Unexpectedly, non-hospitalized patients with confirmed RSV infection also had high levels of cbDVGs and high viral loads. Analysis of the kinetics of cbDVG production revealed that when cbDVGs arise early in infection, less severe symptoms present. In contrast, when cbDVGs arise later in infection, higher viral loads and more severe disease occur. The latter patients also produce higher levels of pro-inflammatory cytokines which likely cause immunopathogenesis.

An interpretation of these findings is that when cbDVGs arise early in infection, they induce antiviral immune responses that limit viral replication and disease. When cbDVGs arise later, the virus has already reproduced to high levels, leading to more severe disease. The factors that regulate cbDVGs production are not known, but could involve sex, age, immune status, and the levels of the defective genomes in the virus inoculum.

These results are of interest because it has not been possible to predict which RSV infected patients will develop severe disease. It might be possible to use levels of cbDVGs to forecast clinical outcome.

When defective viral particles were discovered many years ago, Alice Huang proposed that they might modulate viral pathogenesis. It was not until the 1990s that the technology became available to test this hypothesis. The results with RSV suggest that whether cbDVGs are beneficial or detrimental depends on when they arise in infection.

SARS-CoV-2 variants arise during individual infections

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Early in the COVID-19 pandemic, SARS-CoV-2 genome variation appeared to be low, with an average of 10 base differences in the 30,000 base genome between any two isolates. Late in 2020, as many more people were infected, variants were isolated that had more changes than previously seen. A study of variation at the genome level indicates that diversity in a single host has been underestimated.

SARS-CoV-2 variants certainly arise in each infected individual, and these may be subjected to selection pressures such as those imposed by antibodies binding to spike protein. Commonly used sequencing technologies do not permit detection of virus variants within single samples. To address this limitation, a high-throughput sequencing method was developed for sequencing individual virus RNA genomes in patient samples. The results demonstrate that SARS-CoV-2 variants emerge in each host and are subject to immune selection pressure.

When this method was used to analyze a patient isolate of SARS-CoV-2 after four passages in Vero cells, in the regions encoding spike, ORF3, envelope, and M protein, 18 unique combinations of mutations were detected. Over half of the single genome sequences differed from the reference sequence. Many of the changes led to amino acid substitutions, suggesting selection pressure occurring during cell culture adaptation.

In-host diversity was then examined for 7 patients sampled between days 8 and 17 of illness onset. Only a few sequence haplotypes were detected, with no clear consensus among the amino acid changes. These relatively homogeneous sequences might have been a consequence of sampling early in infection when limited antibody pressure was present. Examination of the antibody response in longitudinal samples revealed an increasing and broadening antibody response to the spike.

A study of antibody responses and presence of mutations in individual genomes revealed a correlation between the emergence of antibodies to the N-terminal domain of spike protein, the emergence of amino acid changes in regions that bind these antibodies, and a delay in clearance of virus. These results are consistent with antibody pressure during infection leading to selection of SARS-CoV-2 spike variants (pictured).

SARS-CoV-2 variation in a single host had not been previously described, probably due to the inability of previous sequencing methods to distinguish variation from technical errors. It is also likely that high-quality data were acquired early in infection when viral titers are high yet antibody pressure is not yet present.

There are several take-home messages from these findings. They illustrate how diversity in a single host might give rise to antibody-resistant variants that could spread in a population if they have the appropriate fitness. In-host escape might be avoided by containing viral reproduction early in infection, either by prior immunity or by antiviral therapy, before selection by antibody takes place. This method should be applied to studying more COVID-19 patient samples to understand the extent of potential in-host SARS-CoV-2 variation.

SARS-CoV-2 variant B.1.1.7 is not more virulent

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coronavirus

When the B.1.1.7 variant of SARS-CoV-2 was first detected in the UK in December 2020 it was accompanied by unsubstantiated claims of increased transmissibility and virulence. The results of a hospital-based study in London reveals no association of the variant with severe disease in this cohort.

In a note published by NERVTAG on 21 January 2021, the panel concluded that ‘there is a realistic possibility that infection with VOC B.1.1.7 is associated with an increased risk of death compared to infection with non-VOC viruses.’ The death risk ratio for VOC infected individuals compared with non-VOC infected individuals was 1.65. This conclusion was based on analysis of COVID-19 related deaths at several hospitals in the UK. The authors noted in this report that ‘The data set used in the LSHTM, Imperial, Exeter and PHE analyses is based on a limited subset of the total deaths. This includes approximately 8% of the total deaths occurring during the study period’.

In the present study, SARS-CoV-2 PCR-positive samples from hospitalized patients were analyzed that had been collected between 9 November and 20 December 2020 in London. Of these, 341 (58%) were infected with B.1.1.7 and 143 (42%) were infected with an ancestral virus. Results of statistical models showed no association between severe disease and death and the B.1.1.7 lineage.

I hope that these results can begin to reverse the disturbing narrative advanced by some that B.1.1.7 is 50% more virulent than its ancestor. This conclusion was never firmly grounded, yet it has been echoed by mainstream media as if it were dogma.

Unfortunately the authors of this paper continue to promote the idea that B.1.1.7 viruses are more transmissible. Their conclusion is based on increased levels of viral RNA in patient samples as determined by RT-PCR (cycle threshold 28.8 in VOC infected patients versus 32.0 in non-VOC infected patients) and genomic reads by sequencing (1280 vs 831). Increased viral load determined by these methods might be an indication of increased viral fitness, but it does not prove increased transmission. It is not known if VOC-infected patients shed more infectious virus, which might be consistent with increased transmission. Until such experiments are done, it can only be speculated that B.1.1.7 and other VOC have increased transmissibility.

A tapeworm drug to treat COVID-19?

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Niclosamide (pictured) is a drug that has been approved in humans to treat infections with a variety of tapeworms. It might be useful for preventing SARS-CoV-2 replication and COVID-19 pathogenesis by inhibiting virus-catalyzed membrane fusion.

Examination of the lungs of 41 patients who died of COVID-19 revealed, in addition to expected lung injury, the presence of syncytia. Such giant cells contain many nuclei and are produced when SARS-CoV-2 infected cells fuse with neighboring, uninfected cells. The fusion occurs when the spike protein of SARS-CoV-2, present on the plasma membrane of infected cells, attaches to the receptor ACE2 on a neighboring cell. This interaction would normally allow virus particles to fuse on entry into cells. In this case, the interaction leads to fusion of neighboring cells. Production of only the spike protein in cells in culture also leads to formation of syncytia.

These observations suggested that a drug that inhibits syncytium formation might help alleviate the severe lung injury observed in some COVID-19 patients. Screening of over 3000 small molecules for their ability to inhibit cell fusion identified a variety of candidates which had in common the ability to regulate intercellular calcium levels. Some of these compounds, such as Niclosamide, inhibited both membrane fusion and virus reproduction.

Niclosamide is an inhibitor of the calcium-activated TMEM16 family of chloride channels. Production of spike in SARS-CoV-2 infected cells leads to activation of TMEM16, which is required for syncytium formation. These observations explain why inhibition of TMEM16 by niclosamide impairs formation of syncytia.

Based on its known activities, activation of TMEM16 by SARS-CoV-2 infection might not only stimulate formation of syncytia, but could also promote inflammation, thrombosis, and diarrhea, the latter through promotion of chloride secretion from cells. Hence the drug might be useful for treating COVID-19 disease and might have efficacy later in infection when antivirals are not effective.

T cells will save us from COVID-19

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In our quest to stop the COVID-19 pandemic by vaccination, we have been myopically focussed on inducing antibodies against the spike protein. As variants of SARS-CoV-2 have emerged that reduce the ability of such antibodies to block infection, concern has arisen that we will not be able to halt the disease. Such concerns appear to ignore the other important arm of the adaptive immune response: T cells.

Anti-viral antibodies can prevent infection of cells, but when antibody titers are low – years after infection or vaccination – some cells will inevitably be infected. In this case, T cells come to the rescue. Cytotoxic T cells can sense that a cell is infected and kill it (illustrated). T cells sense infected cells by virtue of viral peptides that are presented by major histocompatibility molecules on the plasma membrane. Such T cell peptides may be produced from nearly any viral protein. In contrast, only certain viral proteins, like the spike of SARS-CoV-2, can give rise to antibodies that block infection.

The T cell response to SARS-CoV-2 infection has been largely ignored for the past year. Certainly, some laboratories have studied T cell responses in patients, and the vaccine makers have dutifully included them along with assays for neutralizing antibodies. But the dialogue has never included T cells as important for resolving disease – but they are for most viral infections. Because T cells can kill virus infected cells, they can help prevent disease and end the infection.

The recent finding that amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity is very good news. In this study, the authors synthesized short peptides covering the entire proteome of multiple SARS-CoV-2 isolates, including the original Wuhan strain, and variants B.1.1.7, B.1.351, P.1, and CAL.20C. They found little difference in the ability of T cells from either convalescent or vaccinated patients to recognize peptides from these viruses. This result means that the amino acid changes in the variants are not likely to impact the ability of T cells to clear infection.

This observation explains why some COVID-19 vaccines have effectively prevented hospitalization and death even in regions where variants circulate widely. In some cases the ability of sera from vaccinated individuals have reduced ability to neutralize infection with some variants. Nevertheless, the vaccines prevent severe COVID-19 and death because T cells can still recognize variant virus-infected cells and clear them.

It’s highly unlikely that vaccination will prevent infection with SARS-CoV-2. Antibody levels rapidly decline after infection or vaccination, especially in the respiratory mucosa. When a virus enters the nasopharynx of an immune individual, it will encounter little antibody opposition and will initiate an infection. However memory B and T cells will spring into action and within a few days produce virus-specific antibodies and T cells. The antibodies will limit infection while the T cells will clear the virus-infected cells. The result is a mild or asymptomatic infection that likely is not transmitted to others.

The recent observations that vaccination appears to prevent asymptomatic infections is a red herring. These studies are being done soon after vaccination when antibody levels in serum and mucosa are high. If these studies were done a year after immunization, the results would be quite different.

Now imagine that you are fully vaccinated and become infected with a SARS-CoV-2 variant. The virus may begin to reproduce rather well in the nasopharynx even in the face of a memory response, because the antibodies are just not good enough to block infection. T cells to the rescue: the T cell epitopes on the surface of the infected cells are readily recognized because they are mainly the same in the variants as in the ancestral strain of SARS-CoV-2. You may have a mild infection but you will not be hospitalized or die. Isn’t that the goal of vaccination?

Why don’t T cell epitopes change as do B cell (antibody) epitopes? A B cell epitope is the same in everyone and so if a virus emerges with a slightly different epitope, it will evade antibody in anyone infected with that virus. T cell epitopes are different. T cell epitopes are presented to T cells on the infected cell surface by MHC molecules, which are encoded by highly polymorphic genes. That means that your MHC is likely different from mine, and so will be the viral peptides displayed in them. So if a T cell epitope varies during your infection, it won’t matter to other people – their infected cells will be displaying different T cell peptides.

It is possible that SARS-CoV-2 will continue to produce altered spike proteins that will completely evade antibody neutralization. In this case T cells might not be enough to prevent severe disease – they could be overwhelmed by so many infected cells. Our rush to make vaccines – understandable given the urgency – have led us to such a situation. Most of the vaccines were based only on the spike protein. If we change the spike protein to accommodate variants, we might get in a never-ending cycle of changing COVID-19 vaccines on a regular basis. A better approach would be to produce second-generation COVID vaccines that include other viral proteins besides spike protein. Inactivated and attenuated vaccines fall into this category; another solution would be to modify authorized mRNA vaccines to encode additional viral proteins.

Five year persistence of Ebolavirus in humans

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Ebolavirus

The current outbreak of Ebolavirus disease in Guinea, which began in February 2021, may have originated from a survivor of the 2013-16 outbreak in the same country.

Phylogenetic analysis of genome sequences revealed that viruses from the current outbreak group with the Makona variant, which caused the 2013-16 epidemic. The new isolates are most closely related to viruses sampled in the same region in August 2014, differing by only 12 and 13 bases. Consequently the recent outbreak in Guinea was not initiated by a spillover from an animal reservoir, as has been the case for all previously studied Ebolavirus outbreaks. Rather the sequence data indicate that the isolates are somehow linked to the 2013-16 outbreak. However, the number of substitutions – 110 – is far less than would be expected had the viruses been transmitted silently from human to human since that time.

The implication of these data is that Ebolavirus remained undetected in a survivor of the 2013-16 outbreak for 5 years. While Ebolavirus is an acute infection – one that is resolved in the host – the extent of the 2013-16 outbreak revealed rare instances of persistence of the virus in survivors. In once case, an individual who had recovered from the disease developed unilateral uveitis 14 weeks after the onset of Ebolavirus disease and 9 weeks after clearance of viremia. Infectious Ebolavirus was isolated from the aqueous humor. Shortly after the declaration of the end of the Ebolavirus outbreak in December 2015, a new cluster of cases was detected in Guinea in February and March 2016. Genome sequence analysis and epidemiological tracing revealed that these cases all originated from a single individual who harbored infectious Ebolavirus in his testes for over 500 days. He passed the infection on to others during sexual intercourse. In this outbreak the viral genomes differed by just 5 mutations from isolates obtained during the previous outbreak.

These observations indicate that Ebolavirus can persist, for at least 5 years, in an infectious form in immunoprivileged sites such as the vitreous humor of the eye and the testes. The slow evolutionary rate of the genome during such persistent infections – 6 times less than occurs during human to human transmission – implies a very low level of replication. It is remarkable that Ebolavirus retains infectivity for such long periods with so little reproduction.

Such persistent Ebolavirus infections are of concern as they may lead to new outbreaks after many years. The frequency of such persistence can reach 75% of men at 6 months after infection. Antiviral drugs should be developed to eliminate persistent infections in individuals who have recovered from Ebolavirus disease. Individuals harboring virus in semen are easy to identify, but detection of virus in the eye – done by sampling the vitreous humor by needle inserted into the eye – will be more difficult to accomplish.

How vaccines work

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Vaccines work by educating the host’s immune system to recall the identity of a virus years after the initial encounter, a phenomenon called immune memory. Viral vaccines establish immunity and memory without the pathogenic consequences typical of a natural infection. The success of immunization in stimulating long-lived immune memory is among humanity’s greatest scientific and medical achievements.

Immune memory is maintained by dedicated T and B lymphocytes that remain after an infection has been resolved, and most activated immune cells have died. These memory cells can respond rapidly to a subsequent infection (Figure). Ideally, an effective and durable vaccine is one that induces and maintains significant numbers of memory cells. If the host is infected again with this same pathogen, the memory B and T cells initiate a response that rapidly controls the pathogen before disease develops. This paradigm is true for most human viruses for which vaccines exist, including measles, mumps, and varicella-zoster viruses and poliovirus. In some cases, antigenic variation, such as occurs with influenza virus, precludes complete protection by a memory immune response, necessitating re-vaccination.

Protection from Infection or Protection from Disease?

The memory response elicited by most human viral vaccines does not protect against reinfection, but rather against the development of disease. An individual may be exposed repeatedly to viruses and never be aware of it, because the memory response eliminates the virus before signs and symptoms develop. After vaccination with inactivated poliovirus vaccine, virus replication may take place in the intestine, but effectively blocks the development of poliomyelitis. On the other hand, the human papillomavirus vaccine is over 90% effective at blocking infection. Consequently the HPV vaccine induces sterilizing immunity.

Whether or not COVID-19 vaccines will block infection is unknown because it has not been adequately measured. The results of a few small studies suggest that some of the vaccines may prevent infection. However these studies are not conclusive because they are being done shortly after vaccination, when serum antibody levels are much higher than they will be in, say, 6 months. Only then will we have an accurate measure of how well vaccination blocks infection with SARS-CoV-2. I suspect that none of the COVID-19 vaccines will block infection, but will reduce virus reproduction sufficiently to impede transmission in the population.

Population-wide immunity (aka herd immunity)

To be effective, a vaccine must induce protective immunity in a significant fraction of the population. Not every individual in the population need be immunized to stop viral spread, but the number must be sufficiently high to impede virus transmission. Person-to-person transmission stops when the probability of infection drops below a critical threshold. This effect is called herd immunity.

The herd immunity threshold is calculated as 1- 1/R0. R0 is the number of nonimmune individuals that on average will be infected upon encounter with an actively infected individual. As the reproduction number, R0, increases the value of 1/R0 decreases, and thus 1 − 1/R0 gets closer to 1, or 100%. For smallpox virus, the herd immunity threshold is 80 to 85%, while for measles virus (which has a high R0), it is 93 to 95%. Early in the COVID-19 outbreak the R0 of SARS-CoV-2 was calculated to be 2-3, which would produce a herd immunity threshold of 50-70%.

Herd immunity only works when a vaccine either blocks infection, or sufficiently reduces virus reproduction in the host to impede person to person transmission. As stated above, I see no reason why COVID-19 vaccines will not sufficiently reduce transmission to enable herd immunity.

No vaccine is 100% effective at inducing immunity in a population. Consequently, the level of immunity is not equal to the number of people immunized. For example, when 80% of a population is immunized with measles vaccine, about 76% of the population is actually immune, well below the 93 to 95% required for herd immunity.

What about T cells?

For many virus infections, antibodies are crucial for preventing infection. However, resolution of infection often requires the action of cytotoxic T cells, which kill virus infected cells. For vaccines that do not induce sterilizing immunity, it is likely that T cells play a role in eliminating virus-infected cells and preventing the development of disease.

This division of labor has been largely ignored in the discussion of COVID-19 vaccines. Most of the dialog has concerned the induction of antibodies and their ability to neutralize virus infection. COVID-19 vaccines do induce virus-specific T cells and it is likely that these will clear infections that begin in vaccinated indivduals. It has been reported that amino acid changes in SARS-CoV-2 variants of concern do not affect T cell epitopes, and that T cell responses in individuals who have either recovered from infection or have been vaccinated are not affected by these changes. Therefore it seems likely that even if variants of concern are able to overcome to some degree previous antibody immunity, they will be cleared by T cell responses, avoiding severe disease and death. The results of the phase III trial of the J&J COVID-19 vaccine support this presumption.

Understanding virus isolates, variants, and strains

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Many virology terms are being used these days by people who do not understand their meaning. Included are journalists, medical doctors, scientists, lawyers, and people from all walks of life. In normal times this word mis-usage would be so rare that it would not matter. However, because we are in a viral pandemic that affects nearly everyone, I will attempt to explain the meaning of virus isolates, variants, and strains.

Many of the terms used in virology are ill-defined. They have no universally accepted definitions and there is no ‘bible’ with the correct meanings. As each of us are trained by other virologists, we hear them using terms in certain contexts and we copy their usage – whether or not it is correct. I learned many good things from my mentors but also many things that are wrong.

Nevertheless, certain terms should have specific meanings. Some of my colleagues will certainly disagree with some of my definitions, others will agree. Kudos to the latter. I also recognize that few will read this post and it will have little impact. Perhaps one day a high school student will search for some of the terms and come across it. It is mainly meant for me to put my thoughts down in an orderly manner.

The virology terms I have in mind all have to do with attempts to place order on the huge varieties of viruses in the virosphere. Most of them today derive their meaning from the viral genome: the DNA or RNA that encodes the production of new virus particles. This reliance on the genome is relatively recent: until the 1980s we had no genome sequences; hence most categories were based on other properties, such as the size of the virus particle, whether or not it has a membrane, its type of symmetry, and much more. Today it’s all about the genome. Whether or not you think this myopia is a good idea is not the topic of this post.

Let’s start with the term virus isolate, because it’s the easiest to define. An isolate is the name for a virus that we have isolated from an infected host and propagated in culture. The first isolates of SARS-CoV-2 were obtained from patients with pnemonia in Wuhan in late 2019. A small amount of fluid was inserted into their lungs, withdrawn, and placed on cells in culture. The virus in the fluid reproduced in the cells and voila, we had the first isolates of the virus.

Virus isolate is a very basic term that implies nothing except that the virus was isolated from an infected host. An isolate comes from a single host. We can have my virus isolate, or yours, or the neighbor’s down the street. Most patients do not get to have virus isolates taken from them. Even though SARS-CoV-2 has infected millions, we do not have millions of isolates, probably just thousands. We do have genome sequences from many people, and those can be inferred to represent the isolate from each person – however in most cases infectious virus is not isolated from individual patients.

Isolates are given names so that their origin is known. For example, one of the early isolates of SARS-CoV-2 is called BetaCoV/Wuhan/WIV04/2019. This isolate name consists of the genus, Betacoronavirus, followed by the city of origin, the isolate number, and the year. SARS-CoV-2 is the name of the virus; it is not an isolate name. Isolates of other viruses are also precisely named. I’m a big fan of the very detailed influenza virus nomenclature, which is as follows: Virus name/antigenic type/host of origin if other than human/geographical origin/serial number/last two digits (or all four digits) of year of isolation/hemagglutinin subtype neuraminidase subtype. Examples include influenza A virus A/duck/Germany/1868/68 (H6N1) or influenza A virus A/chicken/Vietnam/NCVD- 404/2010 (H5N1).

A virus variant is an isolate whose genome sequence differs from that of a reference virus. No inference is made about whether the change in genome sequence causes any change in the phenotype of the virus. The meaning of variant has become clouded in the era of whole viral genome sequencing, because nearly every isolate may have a slightly different genome sequence. Such is the case for SARS-CoV-2: nearly every sequence from a different person is slightly different. Up until the end of 2020, any SARS-CoV-2 sequences from any two individuals differed by about ten nucleotide changes out of 30,000. They are all variants, but the term is rarely used in this context. However since then viral genomes with many more changes have been identified. These have been called ‘variants of concern’ (VOC) because it is thought that the changes confer new phenotypic properties such as increased fitness. British scientists did a good deed by calling them VOCs, because now the press must call them variants.

Unfortunately mainstream media, following in the footsteps of scientists who really should know better, have been using the term ‘strain’ to describe what are actually variants. This practice emerges in every viral outbreak: there is a new, more (fill in the blank with your favorite phenotype) strain of Ebolavirus, of Zika virus, and now of SARS-CoV-2. It began early in 2020 with the finding of variants with a single amino acid change in the spike protein, from D to G at position 614. The press called this a new strain that was more transmissible. But the use of strain was incorrect: it is a variant and remains so to this day.

A virus strain is a variant that possesses unique and stable phenotypic characteristics. Such characteristics can only be ascertained by the results of experiments done in the laboratory, in cells in culture and in animals, coupled with observations made in infected humans. The name strain is not easily earned: certainly it cannot simply be given by journalists! As Jens Kuhn has written, “The designation of a virus variant as a strain would be the responsibility of international expert groups”. No such designation of strain has been given more than once to SARS-CoV-2: there is one, and only one strain of this virus. No incorrect usage of that term will change this fact. As you might imagine, it can take some time for an international group of experts to agree on anything.

Viral strains are few and far between: it is a designation highly desired but given sparingly. A retrovirologist recently assured me that there is only one strain of HIV-1. The Lansing strain of poliovirus is derived from a human isolate that was passaged 99 times in mice until it acquired the ability to infect that species. That strain has demonstrably different properties from the human strain.

There are other terms to describe viruses but they are more confusing than contentious, and they are not used universally. The term serotype is used to describe viruses of the same species that are antigenically different. There are three serotypes of poliovirus; if you are infected with type 1, then immunity you generate will not protect you against infection with types 2 or 3. Same for the four serotypes of dengue virus, and the hundreds of rhinovirus serotypes. These days, the genome sequence of the virus is used to infer whether isolates are serologically different. The term genotype is used to describe the genetic makeup of a virus. For example, hepatitis C viruses are placed in different genotypes depending on the overall identity of their genomes. For other viruses, the term clade is used. A clade is a group of organisms composed of an ancestor and its descendants, as illustrated by the phylogenetic tree below. SARS-CoV-2 isolates and HIV-1 isolates are placed in clades based on phylogenetic trees constructed from their genome sequences.

I believe that the terms of virology should be used accurately and consistently. The terms isolate, strain, and variant have been frequently and incorrectly misused during the pandemic, which generates confusion. I have little faith that either the general public or the scientists will agree on any nomenclature. Rest assured that if you misuse isolate, variant, or strain, I will correct you according to my lexicon.

SARS-like bat coronaviruses are not only in China

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It is well past the time to stop blaming a laboratory in China for the release of SARS-CoV-2. Such fallacies reflect an ignorance of scientific facts, including the recent finding of closely related coronaviruses in bats in Thailand.

The bat CoV RatG13, sampled in 2013 in Yunnan province, shares 96% whole genome identity with SARS-CoV-2, suggesting a likely bat origin of the pandemic virus. To identify other possible sources for highly related viruses, a colony of 300 bats in eastern Thailand, consisting only of one species, Rhinolophus acuminatus, was sampled in June 2020. Thirteen of 100 bat rectal swab samples were positive for a single PCR amplicon with 95.86% sequence identity to SARS-CoV-2 and 96.21% identity to bat CoV-RaTG13. This virus, named RacCS203, appears to be the dominant coronavirus circulating in this bat colony. Phylogenetic analyses indicate that RacCS203 is a new member of the SARS-CoV-2 related CoV lineage (SC2r-CoV).

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An antiviral to prevent or treat SARS-CoV-2 infection

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Vaccine development has far outpaced antiviral discovery for COVID-19. Hydroxychloroquine was a disaster, and the repurposed remdesivir, which must be administered intravenously, has modest effect when given to hospitalized patients. The situation is unfortunate because antiviral drugs may be used to either prevent infection (prophylactic) or treat infection (therapeutic). A promising antiviral drug candidate is EIDD-2801/MK-4482 which has been shown to block SARS-CoV-2 transmission among ferrets, and more recently, to treat or prevent infection in mice. In both cases the drug is active after oral administration.

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