Archive for the ‘Evolution’ Category
Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap
A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 109 PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4+ T-cell and CD8+ T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4+ T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4+ T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.)
This is a pretty big deal – because it reports an extension of a wholly South African-originated vaccine trial, that consisted of a DNA prime with a subtype C gp150 gene and an artificial Gag-RT-Tat-Nef polyprotein gene, followed by a rMVA boost, that was as immunogenic as anything else trialled around the same time.
I was alerted via Twitter this morning to the fact that the CDC’s Morbidity and Mortality Weekly report that reported the first recognition of the syndrome we now know as AIDS, was published on 5th of June 1981. It appears – sadly – that their archive only goes back to 1982: there’s a missed chance to expose some history, CDC?!
Thirty five years: I was a novice lecturer, just starting out; the Web was still science fiction; HIV and its relatives were still undiscovered – but they had already started to spread out of Africa, after smouldering away in the tropical forests of Gabon and the Congos for decades.
I started an information web page on HIV/AIDS back in 2000 or so, largely in response to the ridiculousness of Thabo Mbeki’s pronouncements on the virus and the disease: thanks to tectonic shifts in the UCT Web policy, these disappeared – but thanks to the invaluable Wayback Machine, can still be found. If you want a slice of history, and to see how bad I am at designing web pages, go take a look. Still MOSTLY valid, although many of the links are now dead – sic transit the web content, unfortunately!
And here we are in 2016: I’m now an elderly academic, the Honours student who alerted me to the fact the the “GRIDS” syndrome virus may have been identified in 1983 is now a senior Professor and distinguished HIV researcher – there’s a whole career there, Carolyn! – and HIV/AIDS is still with us. And unfortunately, Thabo Mbeki is still being wilfully if not malevolently ignorant, and I am still feeling it necessary to crap on him.
At least the pandemic appears to have peaked in terms of incidence, and ARVs are increasingly good and employed widely; however, we still don’t have a decent vaccine, and people are still being infected. This pandemic will last out my career – but hopefully not those of some of the people I have trained.
The means of engineering potentially deadly avian influenza is freely available on the internet.
Despite continuing global efforts to contain avian influenza, or bird flu, the means of engineering this potentially deadly H5N1 virus to render it transmissible to humans is freely available on the internet. So too are similar instructions for engineering a virus like the “Spanish flu”, which killed some 50 million people in the pandemic of 1918-19.
The digital floodgates opened in 2011 when a peak US regulatory watchdog came down in favour of scientists seeking to publishing their work engineering the H5N1 virus. The decision to uphold such “scientific freedom” was and remains, highly contentious among the global scientific community. Its implications, however, are readily available as online “recipes” for potentially dangerous viruses, which add a new risk to the already considerable challenges of maintaining global biosecurity in the 21st century. For all the recent advances in biomedical science, drugs, vaccines and technology, this is a challenge we remain ill-equipped to meet.
Read more: http://www.theage.com.au/comment/online-recipes-for-contagious-diseases-means-australias-bioterrorism-threat-is-real-20151208-gli97v.html#ixzz3tvWn63AE ;
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Sourced through Scoop.it from: www.theage.com.au
OFFS: seriously! Again?! Someone else has just discovered that entire virus genomes are freely available via PubMed, along with papers on gain-of-function experiments, and immediately leaps to the conclusion that this means “…the means of engineering this potentially deadly H5N1 virus to render it transmissible to humans is freely available on the internet”.
I’m sorry, this is being simple-minded to the point of parody. I have written elsewhere – here in ViroBlogy, and in Nature Biotech’s Bioentrepreneur blog section – on how it is MOST unlikely that bearded fellows in caves in Afghanistan or remote farms in Montana are going to whip up weaponised batches of H5N1 flu or Ebola.
Yes, the papers are available; yes, the sequences necessary to make a potentially (and I say potentially advisedly) deadly virus are available online; yes, one can bypass the blocks on getting resynthesised genes in developing countries (hint: China).
But could anyone outside of a sophisticated lab environment use these to make anything nasty?
Just think about what you would need to make weaponised flu, for example. There are two ways to go here, these being the totally synthetic route (“mail order” DNA – HATE that term!), with some serious molecular biology and cell culture at the end of it, and the “natural” route – which would involve getting a natural and nasty isolate of H5N1 / H7N9 / H9N2, and being able to culture it and engineer it as well.
Both routes require a minimum of a serious 4-yr-degree-level training in microbiology / mol biol, as well as laboratory resources that would include incubators, biohazard cabinets, and disposables and reagents that are not on your normal terrorist’s priority purchase list.
In fact, the kinds of resources you’d find at a University or Institute Infectious Disease unit – or state-sponsored biowarfare lab.
Seriously, now: in order to use the information that is “freely available”, you’d have to do what amounts to an entire postgrad degree’s worth of work just to set up the kinds of reverse genetics necessary to WORK with recombinant flu, presuming you already had an isolate, and even more than that if you were to start with synthesised DNA and try to recreate infectious virus.
Again, this is the kind of work they do in biowarfare / biodefence labs (funny how they’re pretty much the same thing, isn’t it?) – because it’s finicky, expensive, laborious – and potentially dangerous to the researcher.
And it’s interesting that the only rumoured escapes of biowarfare agents have been of flu in 1977 in the old Soviet Union, and of anthrax in Sverdlovsk in the USSR in 1979. And in the US in 2001, and again in 2014. ALL of them from official facilities, I will discreetly point out.
Oh, there have been rumours that Saddam’s Iraq weaponised camelpox; that the USSR/Russia cloned Ebola into a poxvirus; that Al-Qaeda tested anthrax – but the first two took state resources, and if the third happened at all, it’s nothing that the UK and USA and friends hadn’t already done in the 1940s.
IT IS NOT THAT EASY TO MAKE RECOMBINANT VIRUSES.
Like my recent books on History of Viruses and Influenza, I’m constructing an ebook Introduction to Virology textbook – and I’d like people’s opinions.
It’s going to look something like this:
It will be based on my web pages that were so cruelly destroyed, but will be PROFUSELY illustrated, using all of the bells and whistles built into the iBooks Author app, with liberal use of Russell Kightley’s very excellent virus picture library.
And I will sell it for US$20 or less.
Tell me what you think of the taster – and there will be more.
Rinderpest, or cattle plague, was declared eradicated in 2011. But many research institutes still have samples of the rinderpest virus in storage. Disease experts want those samples destroyed.
Sourced through Scoop.it from: www.npr.org
And if they haven’t yet, despite years of debate, why should rinderpest virus stocks?
Consider: we have an effective vaccine(s); we still have the related peste des petits ruminants virus knocking around, with vaccines to it – so why shouldn’t stocks of the live virus strains be preserved?
How many viruses have in fact made it out of fridges, and back into the world? Well, there was that purported 1977 H1N1 release in Russia/Mongolia…but can anyone think of another well-documented one? Just one?
The fact is that it is FAR easier to deliberately spread endemic viruses around – like foot-and-mouth disease virus – than it would be to reactivate and spread something from a lab freezer.
Rather let us conduct an inventory of who has what, consolidate it like they did with smallpox, and forget about the unknowable, which is obscure freezers in far-flung rural centres where no-one remembers what is there – and where powercuts have probably thawed the samples more than once.
Maize streak Reunion virus (MSRV) is a member of the Mastrevirus genus in the family Geminiviridae. Of the diverse and increasing number of mastrevirus species found so far, only Wheat dwarf virus and Sweetpotato symptomless virus 1 have been discovered in China. Recently, a novel, unbiased approach based on deep sequencing of small interfering RNAs followed by de novo assembly of siRNA, has greatly offered opportunities for plant virus identification.
Image of a mastrevirus from Ed Rybicki
This is quite a big deal: there are very few cereal-infecting geminiviruses described from Eurasia, let alone symptomatic maize-infecting mastreviruses whose closest relatives come from Isle de la Reunion in the South Indian Ocean and Nigeria.
Mastreviruses are not seed-transmitted, so how did it get there? What is transmitting it? Is it possibly the elusive Bajra streak virus from India, that was described but never sequenced?
The authors say, in their conclusion:
“To date, other than MSV, MSRV is the only mastrevirus species that has ever been sampled from maize having maize streak disease symptoms. Interestingly, MSRV was also detected from wild grasses such as Setaria barbata and Rottboellia sp. in Nigeria, suggesting expanded host and geographical ranges for this virus . This first report of MSRV isolates in China reveals that this virus is likely to possess a far greater diversity and distribution than has been appreciated. Because 10 of 22 samples from Yunnan Province, China, were infected with MSRV-YN, for an infection rate of 45.5 %, further work on epidemics of MSRV-YN in China is needed.”
Absolutely! Maize streak, whether caused by MSV or potentially by MRSV, can be a devastating disease – and if this is expanding out of endeminicty in grasses thanks to leafhopper population expansion, or climate change, things could get interesting int hat part of the world.
This question has come up in my life innumerable times in the last 40 years that I have been interested in viruses – and I find that debate on it often becomes theological in its intensity, with proponents muttering things like “They’re just intracellular parasitic molecules!”, or “Of course they’re alive – they evolve, don’t they?”
And as happens when I hear theological arguments, my eyes glaze over, and I think of other things.
Because it’s really quite simple: as I have been patiently explaining to students for over thirty years now, viruses are simply acellular organisms – which find their full being inside host cells, where some measure of essential support services are offered in order to keep the virus life cycle turning. What everybody sees as “viruses” are in fact virions, the particles that viruses cause to be made in order to transport their genomes between cells, and to preserve them while doing so. Thus, in a very real sense a virus IS the cell it infects – because it effectively takes the latter over, and uses it to make portable versions of the genome that can infect other cells.
Back in 1995 or so, I wrote the following for my first teaching pages:
The concept of a virus as an organism challenges the way we define life:
- viruses do not respire,
- nor do they display irritability;
- they do not move
- and nor do they grow,
- however, they do most certainly reproduce, and may adapt to new hosts.
By older, more zoologically and botanically biased criteria, then, viruses are not living. However, this sort of argument results from a “top down” sort of definition, which has been modified over years to take account of smaller and smaller things (with fewer and fewer legs, or leaves), until it has met the ultimate “molechisms” or “organules” – that is to say, viruses – and has proved inadequate.
If one defines life from the bottom up – that is, from the simplest forms capable of displaying the most essential attributes of a living thing – one very quickly realises that the only real criterion for life is:
The ability to replicate
In fact, I have just uncovered something I started writing in 2005 on the same subject:
Fruits of the Bushes of Almost-Life: A Natural History of Viruses
It is an amazing thing that when people speak or write of “life”, they generally miss out one of the most interesting and diverse facets of it: viruses…!
Viruses are like the black sheep of the family of life: they are everywhere, they infect everything, they are the most diverse organisms on our planet, and yet most biologists either do not mention them, or simply dismiss them as “parasites that you can’t even see with a microscope”.
Consider this: of the seven different kinds of genetic material shared by all organisms, all cellular life has only one – and viruses have all seven.
And this: the most abundant and genetically diverse organisms in the oceans, and therefore probably on the planet, are viruses.
Or this: viruses may be the only bridge left to understanding how our DNA-dominated cellular world came to be, from primitive RNA-genomed ancestors.
Let’s face it, viruses generally get a bad press: if it’s not “Will avian flu kill us all?”, it’s “Marburg virus outbreak threatens Luanda”, or “Is SARS coming back?” leaping out at us from our local newspapers – and that’s all just this year. We even have speculation that global warming could unleash long-frozen plagues on us, as viruses thaw out of the Greenland icecap – and while all of this represents media hype, there are grains of truth in all of it, Yes, the H5N1 influenza virus epidemic in poultry is a matter for very serious concern; yes, there was a chance that Marburg virus – an equally nasty relative of the dreaded Ebola – could have devastated Angola’s capital as recently as a few months ago; yes, epidemiologists are worried that SARS coronavirus may again leap out of its animal or even possibly human reservoirs and into the world and kill thousands; yes, long-frozen viruses may yet represent an unexpected and unwelcome disease threat to humanity, its crops and its livestock.
However, all of these concerns highlight only one facet of the complex phenomenon that is viruses: that is, the “viruses as ogre” side of these organisms. Not that this is not amply justified: the single biggest killer of humans this year will probably be either diarrhoea-causing viruses or HIV; the legendary Black Plague that repeatedly decimated medieval Europe may well have been a haemorrhagic fever virus rather than a bacterial disease, and the “Spanish Flu” pandemic of 1918-1922 is now known to have killed more than 60 million people. But viruses also possibly gave us the ability to develop a placenta and develop away from marsupials to become mammals – and viruses probably also regulate the lifetimes of algal blooms, cholera epidemics, aphids, moths that attack conifers, and possibly every living thing in the seas.
In short, viruses are intimately intertwined into every ecological web on this planet, whether we know it or not – and we find out more and more how much this is true the more we look.
What are Viruses?
The very nature of viruses severely taxes all conventional notions of what is an organism, or even of what is life. While the debate on whether viruses are living or are indeed organisms gets almost theological in its intensity in certain biological circles, there is a very simple way around the problems – and that is to regard them as a particle/organism duality, much as physicists have learned to do with the dual wave/particle nature of light.
Quite simply, viruses are obligate intracellular parasites which use the resources of living cells to multiply their genetic material, and to make specialised particles which serve to protect and transport the genetic material, or genome, to other susceptible cells. Their dual nature is defined by the two ends of their life cycle: the virus as organism is inextricably mixed into infected cells, integrated into pathways of nucleic acid and protein synthesis; the virus as particle can be purified away from all cellular components and kept in a bottle like a chemical, totally inert, until you decide to reintroduce it to its host cells.
“The idea that virus and virion are distinct was first proposed by Bandea in 1983. He suggested that a virus is an organism without a cohesive morphological structure, with subsystems that are not in structural continuity…Viruses are presented as organisms which pass in their ontogenetic cycle through two distinctive phenotypic phases: (1) the vegetative phase and (2) the phase of viral particle or nucleic acid. In the vegetative phase, considered herein to be the ontogenetically mature phase of viruses, their component molecules are dispersed within the host cell. In this phase the virus shows the major physiological properties of other organisms: metabolism, growth, and reproduction”
OK, I think I said pretty much the same thing in teaching in 1981, but less elegantly, and I have no proof other than ooooold overhead projection slides B-) He goes on, though, to mention in the context of mimiviruses, that
“Claverie suggested that the viral factory corresponds to the organism, whereas the virion is used to spread from cell to cell.”
This crystallises things nicely: viruses are acellular parasites which take over a cell, and make specialised particles (virions) to spread their genomes. Qualitatively, this is exactly what seeds and spores of plants and fungi do: they make specialised vehicles that preserve their genomes, and which can respond to changes in their environment to initiate a new organism.
However, it’s in his last point that Racaniello gets sufficiently theological to silence some of the doubters. He writes:
“Raoult and Forterre have therefore proposed that the living world should be divided into two major groups of organisms, those that encode ribosomes (archaea, bacteria and eukarya), and capsid-encoding organisms (the viruses).”
I like that. I like it a lot. It makes a lot of sense. And in the light of my last two posts in ViroBlogy – on “The Bushes of Life“, and Deep Evolution of Viruses – I can see that the time has come to spread The True Gospel of Virology.
Which is that viruses are alive. You OK with that?!
Ian Mackay of Virology Down Under fame (or notoriety B-) today alerted me to a new paper on the evolution of viruses – which is being touted via press releases as being something that “…adds to evidence that viruses are alive”.
To my mind at least, it does nothing of the sort: what it does do is provide evidence via the medium of comparison of protein folds that “…implies the existence of ancient cellular lineages common to both cells and viruses before the appearance of the “last universal cellular ancestor” that gave rise to modern cells”.
Arshan Nasir and Gustavo Caetano-Anollés took advantage of the fact that protein structure is at least 3 to 10 times more conserved than sequence, and analysed all of the known folds in 5080 organisms, including 3460 viruses. They identified 442 protein folds shared between cells and viruses, and 66 that are unique to viruses – indicating that virus proteomes truly are more diverse than cellular proteomes.
The press release is rather annoying in places, such as in this excerpt:
“Some giant viruses also have genes for proteins that are essential to translation, the process by which cells read gene sequences to build proteins, Caetano-Anollés said. The lack of translational machinery in viruses was once cited as a justification for classifying them as nonliving, he said.
“This is no more,” Caetano-Anollés said. “Viruses now merit a place in the tree of life. Obviously, there is much more to viruses than we once thought.””
Well, some of us have thought a lot more of viruses for a lot longer, obviously! I have taught for years, for example, that viruses are alive – and just last week this blog has a post on how “The” Tree of Life should in fact be a garden, with a tree and a whole lot of bushes.
I do like this bit from the paper itself, however:
“The most parsimonious hypothesis inferred from proteomic data suggests that viruses originated from multiple ancient cells that harbored segmented RNA genomes and coexisted with the ancestors of modern cells.”
The authors have come up with a REAL Tree of Life, as well – one that includes viruses. Smart folk B-)