Given the deadly global rampage that HIV has been on for the past few decades, you’re all probably familiar with the virus. But you may not be aware that there are two types of HIV—HIV-1 and HIV-2—with the former being significantly more prevalent worldwide. The most common type of HIV-1 is then further divided into distinct subtypes, some of which are associated with a more rapid progression to AIDS. If these different viruses meet in an infected person, for example if someone infected with one subtype is exposed to a different one, they can exchange bits of their genetic material to create a new virus.
One of these so called “circulating recombinant forms” is currently spreading through Cuba, and it’s unfortunately extremely aggressive. Individuals infected with this hybrid virus, which is a mix of three different HIV-1 subtypes, progress to AIDS more than three times faster than average. Now, scientists have scrutinized this particularly pathogenic strain, which has yielded insight into the traits that have bestowed it with this deadly efficiency. The findings have been published in EBioMedicine.
Before HIV can get inside our cells, it first needs to bind to receptors on the surface called CD4. While this is an essential first step, it’s insufficient to get the virus inside. This is where anchoring points, called coreceptors, come in, which HIV also has to latch onto to gain entry. There are two coreceptors, CCR5 and CXCR4, and around 90% of newly transmitted HIV uses the former.
CXCR4-using viruses emerge in around 50% of individuals, but this usually takes around five years from infection. These viruses are associated with a more pronounced depletion of immune cells, but whether this shift in coreceptor preference is a cause or consequence of disease progression is unknown. Interestingly, however, the aggressive recombinant currently spreading through Cuba starts to use CXCR4 very early on in infection, and researchers think this is likely contributing to the observed rapid progression to AIDS.
To find this out, researchers examined 73 recently infected patients in Cuba, 52 who had rapidly progressed to AIDS within three years and 21 without AIDS. Then, they compared the blood of these individuals with 22 patients who had progressed to AIDS after the period typically expected, which is around 10-15 years without treatment.
They found that all those who had progressed to AIDS within three years of infection were infected with a recombinant called CRF19, which is a mixture of subtypes A, D and G. Interestingly, infection with A/D recombinants has previously been reported to result in rapid progression to AIDS, but no CRFs had been exclusively associated with rapid progression. Furthermore, those infected with CRF19 had abnormally high levels of an immune response molecule called RANTES, which acts by binding to CCR5. Without this coreceptor available for binding, CRF19 may have been forced to bypass that anchor point and go straight for CXCR4. Since the switch to CXCR4 usage is associated with progression to AIDS, this could explain why those infected with CRF19 developed AIDS so early on.
Another reason that CRF19 might be so pathogenic is that it has an enzyme, called protease, from subtype D, which is known to be very efficient. This enzyme helps the virus form mature particles, which is an essential stage in the virus life cycle.
A new class of antibiotic has been discovered thanks to a new technique that could yield more of the same – an incredible boon in our fight against antimicrobial resistance.
Scientists in the US have discovered a new class of antibiotic that has been shown to kill Staph and Strep throat infections in mice. They say the way it kills bacteria will make it very difficult for them to evolve resistance in response to the attacks.
Last month, a report chaired by US economist Jim O’Neill predicted that 300 million people will die prematurely by the year 2050 thanks to antimicrobial resistance, if nothing is done to solve the problem. The report went on to add that our global GDP would dip by 0.5 percent by 2020 and will end up 1.4 percent smaller by 2030, purely due to the steady march of resistant bacteria.
In 2013, the chief medical officer of the UK, Sally Davies, announced that antimicrobial resistance would be put on the government’s national risk register of civil emergencies, to join the equally serious threats of terrorism, the pandemic flu, and major flooding.
Antimicrobial resistance is a huge problem, but we might finally have the upper hand in this power struggle between man and bug – a new antibiotic called teixobactin, which has been shown to kill a wide range of drug-resistant bacteria in lab mice, including those responsible for tuberculosis and septicaemia, plus Clostridium difficile colitis (C. dif) – the most common gut bug infection.
“Teixobactin kills exceptionally well. It has the ability to rapidly clear infections,” lead researcher and director of the Antimicrobial Discovery Centre at Northeastern University, Kim Lewis, told Ian Sample at The Guardian.
The secret to Teixobactin’s success is that it prevents microbes from being able to construct their cell walls, and holes in your cell walls means certain death. In fact, the antibiotic ended up killing 100 percent of the bacteria it came into contact with, and no survivors means there’s no one to evolve resistance. “That’s an Achilles’ heel for antibiotic attack,” the researcher who discovered this ability, Tanja Schneider from the University of Bonn, told Sample. “It would take so much energy for the cell to modify this, I think it’s unlikely resistance will appear this way.”
As Kelly Servick explains at Science Magazine, resistance usually occurs when a fraction of a population of microbes somehow survives an antibiotic attack because of a particular mutation, and then those mutated bacteria multiply into a separate resistant population.
“My guess is that if resistance is going to develop against Teixobactin, it will take more than 30 years for that to occur,” Lewis told CBS News.
Not only did Teixobactin kill off 100 percent of the bacteria it came into contact with, including Staphylococcus aureus (Staph infection) and Streptococcus pneumoniae (Strep throat), but it cleared these infections without any side-effects.
Which is all great, but perhaps even more exciting is how the antibiotic was discovered. “Most antibiotics are isolated from bacteria or fungi that churn out lethal compounds to keep other microbes at bay,” says Sample at The Guardian. “But scientists have checked only a tiny fraction of bugs for their ability to produce potential antibiotics because 99 percent cannot be grown in laboratories.”
Since the first antibiotic, Penicillin, was discovered by accident in 1928 by Alexander Fleming, scientists haven’t had a particularly efficient way of finding more. But recently, Kim Lewis’s team developed a device they’re calling the iChip, which can culture bacteria in their natural habitat – in this case, dirt. Bacteria are inserted into the device between two permeable sheets and dug into the ground, where the bacteria are free to grow into colonies as they would in the wild, except for the fact that they’re confined to their iChip chambers.
After two weeks, the researchers retrieved their iChip and were able to test the colonies that had grown in their natural habitat. “To do this, they covered the top of the iChip with layers of pathogens,” says Sample. “Bugs that produced natural antibiotics revealed themselves by killing the pathogens above them.”
The team paired up with NovoBiotic, a Massachusetts-based pharmaceuticals start-up, and researchers at the University of Bonn, and screened 10,000 different types of soil bacteria – cultured in the iChip – for antibiotics. They found 25 new antibiotic compounds, teixobactin being the most high-achieving of the lot. They published their results in Nature today.
Servick reports at Science Magazine that Teixobactin was so effective, it also outperformed Vancomycin – the antibiotic we currently rely on to treat methicillin-resistant Staphylococcus aureus (MRSA) – by a factor of 100. “In mice infected with MRSA, injections of teixobactin led to a 100 percent survival rate at lower doses than vancomycin,” she says.
It’s exciting stuff, but it’s still going to be a while before people can be treated with the antibiotic. Human trials are set to begin in about two years, and if they go well, development for the market will follow.
“Another shortcoming of Teixobactin is that it only works against bacteria that lack outer cell walls, known as Gram-positive bacteria, such as MRSA, Streptococcus and TB,” says Sample at The Guardian. “It doesn’t work against Gram-negative bacteria, which include some of the most worrying antibiotic-resistant pathogens, such as Klebsiella, E. coli and Pseudomonas.”
But hopefully that’s something Lewis’s team’s new iChip method will help solve.
“Any report of a new antibiotic is auspicious, but what most excites me about the paper is the tantalising prospect that this discovery is just the tip of the iceberg. Most antibiotics are natural products derived from microbes in the soil. The ones we have discovered so far come from a tiny subset of the rich diversity of microbes that live there.
Lewis et al. have found a way to look for antibiotics in other kinds of microbe, part of the so-called microbial ‘dark matter’ that is very difficult to study.”
Malaria parasites invade human red blood cells, they then disrupt them and infect others. Researchers at the University of Basel and the Swiss Tropical and Public Health Institute have now developed so-called nanomimics of host cell membranes that trick the parasites. This could lead to novel treatment and vaccination strategies in the fight against malaria and other infectious diseases. Their research results have been published in the scientific journal ACS Nano.
For many infectious diseases no vaccine currently exists. In addition, resistance against currently used drugs is spreading rapidly. To fight these diseases, innovative strategies using new mechanisms of action are needed. The malaria parasite Plasmodium falciparum that is transmitted by the Anopheles mosquito is such an example. Malaria is still responsible for more than 600,000 deaths annually, especially affecting children in Africa (WHO, 2012).
Artificial bubbles with receptors
Malaria parasites normally invade human red blood cells in which they hide and reproduce. They then make the host cell burst and infect new cells. Using nanomimics, this cycle can now be effectively disrupted: The egressing parasites now bind to the nanomimics instead of the red blood cells.
Researchers of groups led by Prof. Wolfgang Meier, Prof. Cornelia Palivan (both at the University of Basel) and Prof. Hans-Peter Beck (Swiss TPH) have successfully designed and tested host cell nanomimics. For this, they developed a simple procedure to produce polymer vesicles – small artificial bubbles – with host cell receptors on the surface. The preparation of such polymer vesicles with water-soluble host receptors was done by using a mixture of two different block copolymers. In aqueous solution, the nanomimics spontaneously form by self-assembly.
Blocking parasites efficiently
Usually, the malaria parasites destroy their host cells after 48 hours and then infect new red blood cells. At this stage, they have to bind specific host cell receptors. Nanomimics are now able to bind the egressing parasites, thus blocking the invasion of new cells. The parasites are no longer able to invade host cells, however, they are fully accessible to the immune system.
The researchers examined the interaction of nanomimics with malaria parasites in detail by using fluorescence and electron microscopy. A large number of nanomimics were able to bind to the parasites and the reduction of infection through the nanomimics was 100-fold higher when compared to a soluble form of the host cell receptors. In other words: In order to block all parasites, a 100 times higher concentration of soluble host cell receptors is needed, than when the receptors are presented on the surface of nanomimics.
“Our results could lead to new alternative treatment and vaccines strategies in the future”, says Adrian Najer first-author of the study. Since many other pathogens use the same host cell receptor for invasion, the nanomimics might also be used against other infectious diseases. The research project was funded by the Swiss National Science Foundation and the NCCR “Molecular Systems Engineering”.
More information: Adrian Najer, Dalin Wu, Andrej Bieri, Françoise Brand, Cornelia G. Palivan, Hans-Peter Beck, and Wolfgang Meier. “Nanomimics of Host Cell Membranes Block Invasion and Expose Invasive Malaria Parasites.” ACS Nano, Publication Date (Web): November 29, 2014 | DOI: 10.1021/nn5054206
Scientists have recreated a nearly exact replicate of the deadly flu virus that killed an estimated 50 million in the 1918 Spanish flu pandemic.
But don’t worry, they say it’s totally safe.
Researchers at the University of Wisconsin-Madison reverse engineered an influenza virus from a similar one found in birds, combining several strains to create one that is nearly identical to the one that caused the 1918 outbreak. They then mutated the genes to make it airborne, and to study how it spreads between animals.
“Our research indicates the risks inherent in circulating avian influenza viruses,” Yoshihiro Kawaoka, the scientist who led the research team, told VICE News. “Continued surveillance of avian influenza viruses — and not only viruses that we know pose risks for humans, such as H5N1 and H7N9 influenza viruses, and attention to pandemic preparedness measures is important.”
According to the statement summarizing the project published this week, the “analyses revealed the global prevalence of avian influenza virus genes whose proteins differ only a few amino acids from the 1918 pandemic influenza virus, suggesting that 1918-like pandemic viruses may emerge in the future.”
In other words, a common avian flu virus that has been circulating in wild ducks is pretty much the exact same one that infected humans a century ago. And now is in a lab.
The research was funded by the National Institute of Health as a way to find out more about similar virus’ and their transmissibility from animals to humans. It was done in a lab that complied with full safety and security regulations, said Carole Heilman, director of the Division of Microbiology and Infectious Diseases, at National Institute of Allergy and Infectious Diseases (NIAD), a division of NIH.
“It was an question of risk versus benefit,” Heilman told VICE News. “We determined that the risk benefit ratio was adequate if we had this type of safety regulations.”
But many scientists disagree and have condemned research that recreates virus’ such this, stating that if released accidentally, a virus could spread to humans and cause a pandemic. Marc Lipsitch, an epidemiologist at Harvard, has criticized research such as Kawaoka’s as unnecessarily risky.
“There is a quantifiable possibility that these novel pathogens could be accidentally or deliberately released. Exacerbating the immunological vulnerability of human populations to PPPs is the potential for rapid global dissemination via ever-increasing human mobility,” Lipsitch said in a paper about experiments with transmissible virus’. “The dangers are not just hypothetical.”
Lipsitch points out that many of the H1N1 flu outbreaks that have occurred between 1977 and 2009 were a result of a lab accident.
Kawaoka disagrees, saying, “We maintain that it is better to know as much as possible about the risk posed by these viruses so we may be able to identify the risk when viruses with pandemic potential emerge, and have effective countermeasures on-hand or ready for development.”
photo credit: James D. Gathany/CDC
Over 200 million people are infected by malaria each year, and the majority of the 627,000 deaths per year are children younger than five. The disease is carried by mosquitos who act as vectors for the parasite. It’s only transmitted to humans by female mosquitoes, as they’re the only ones who bite. A team of researchers led by Andrea Crisanti of the Imperial College London managed to genetically modify mosquitos to produce 95% male offspring, eliminating mosquito populations along with the risk of malaria. The results of the study were published in Nature Communications.
In most species of mosquito, the females need a blood meal in order to acquire the nutrients to create viable eggs. When she does, she can lay about 200 eggs at a time in water, and up to 3,000 eggs over the course of her lifetime. About half of those offspring will be daughters, many of whom will live long enough to produce that amount of offspring also. For humans living near mosquitos carrying the parasite that causes malaria, those numbers of female mosquitos present a very real threat.
But what if the numbers could be skewed so that the sex ratio favors males, who are harmless to humans? This is exactly what Crisanti’s team set out to do with Anopheles gambiae, a species of mosquito endemic to sub-Saharan Africa, where 95% of malaria deaths occur. The researchers modified the males with the enzyme I-Ppol, which excises the X chromosome during spermatogenesis. This renders sperm that would produce daughters to be non-functional, while the sperm that will create male offspring are unaffected. As a result, about 95% of the resulting offspring are male.
Next, modified males were introduced to five caged wild-type populations. As the males mated with the females, they passed along the same mutation until it dominated the population. For four of the five populations, it took only six generations for the mosquitos to die out due to a lack of females.
“What is most promising about our results is that they are self-sustaining,” co-author Nikolai Windbichler said in a press release. “Once modified mosquitoes are introduced, males will start to produce mainly sons, and their sons will do the same, so essentially the mosquitoes carry out the work for us.”
This study was the first to successfully manipulate mosquito sex ratios, and it was done in a big way. The researchers hope that this information will be used to develop genetic mutations to be used in the wild, bringing large populations of mosquitos to their knees.
“The research is still in its early days, but I am really hopeful that this new approach could ultimately lead to a cheap and effective way to eliminate malaria from entire regions,” added lead author Roberto Galizi. “Our goal is to enable people to live freely without the threat of this deadly disease.”
Of course, while eradicating the mosquitos would be fantastic for eliminating the threat of malaria, what other affects would it have? Wouldn’t there be harsh consequences for the ecosystem? After all, mosquitos have been on the planet for about 100 million years and represent 3,500 species. As it turns out, mosquitos wouldn’t really be missed if they were to disappear. While mosquitos can act as pollinators as well as a food source for other animals, their absence would be merely a temporary setback before another species filled the niche. Of course, there is a gamble in assuming the replacement organism would be harmless.
“Malaria is debilitating and often fatal and we need to find new ways of tackling it. We think our innovative approach is a huge step forward. For the very first time, we have been able to inhibit the production of female offspring in the laboratory and this provides a new means to eliminate the disease,” Crisanti explained.
Each year, sub-Saharan Africa loses about $12 billion in economic productivity due to malarial infections. Considering developed areas in these countries have per capita incomes of about US$1500, this would have very real implications for the quality of life for people in those areas. Eliminating that disease would also allow doctors and hospitals to address other health concerns, and the environment would likely benefit from not having to use insecticides.
Galizi, R. et al. 2014. ‘A synthetic sex ratio distortion system for the control of the human malaria mosquito’. Nature Communications, 10 June 2014.
Researchers have identified a new virus in patients with severe brain infections in Vietnam. Further research is needed to determine whether the virus is responsible for the symptoms of disease.
The virus was found in a total of 28 out of 644 patients with severe brain infections in the study, corresponding to around 4%, but not in any of the 122 patients with non-infectious brain disorders that were tested.
Infections of the brain and central nervous system are often fatal and patients who do survive, often young children and young adults, are left severely disabled. Brain infections can be caused by a range of bacterial, parasitic, fungal and viral agents, however, doctors fail to find the cause of the infection in more than half of cases despite extensive diagnostic efforts. Not knowing the causes of these brain infections makes public health and treatment interventions impossible.
Researchers at the Oxford University Clinical Research Unit, Wellcome Trust South East Asia Major Overseas Programme and the Academic Medical Center, University of Amsterdam identified the virus, tentatively named CyCV-VN, in the fluid around the brain of two patients with brain infections of unknown cause. The virus was subsequently detected in an additional 26 out of 642 patients with brain infections of known and unknown causes.
Using next-generation gene sequencing techniques, the team sequenced the entire genetic material of the virus, confirming that it represents a new species that has not been isolated before. They found that it belongs to a family of viruses called the Circoviridae, which have previously only been associated with disease in animals, including birds and pigs.
Dr Rogier van Doorn, Head of Emerging Infections at the Wellcome Trust Vietnam Research Programme and Oxford University Clinical Research Unit Hospital for Tropical Diseases in Vietnam, explains: “We don’t yet know whether this virus is responsible for causing the serious brain infections we see in these patients, but finding an infectious agent like this in a normally sterile environment like the fluid around the brain is extremely important. We need to understand the potential threat of this virus to human and animal health.”
The researchers were not able to detect CyCV-VN in blood samples from the patients but it was present in 8 out of 188 fecal samples from healthy children. The virus was also detected in more than half of fecal samples from chickens and pigs taken from the local area of one of the patients from whom the virus was initially isolated, which may suggest an animal source of infection.
Dr Le Van Tan, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, said: “The evidence so far seems to suggest that CyCV-VN may have crossed into humans from animals, another example of a potential zoonotic infection. However, detecting the virus in human samples is not in itself sufficient evidence to prove that the virus is causing disease, particularly since the virus could also be detected in patients with other known viral or bacterial causes of brain infection. While detection of this virus in the fluid around the brain is certainly remarkable, it could still be that it doesn’t cause any harm. Clearly we need to do more work to understand the role this virus may play in these severe infections.”
The researchers are currently trying to grow the virus in the laboratory using cell culture techniques in order to develop a blood assay to test for antibody responses in patient samples, which would indicate that the patients had mounted an immune response against the virus. Such a test could also be used to study how many people in the population have been exposed to CyCV-VN without showing symptoms of disease.
The team are collaborating with scientists across South East Asia and in the Netherlands to determine whether CyCV-VN can be detected in patient samples from other countries and better understand its geographical distribution.
Professor Menno de Jong, head of the Department of Medical Microbiology of the Academic Medical Centre in Amsterdam said: “Our research shows the importance of continuing efforts to find novel causes of important infectious diseases and the strength of current technology in aid of these efforts.”
Journal reference: L.V. Tan et al . Identification of a new cyclovirus in cerebrospinal fluid of patients with acute central nervous system infections. mBio, June 2013. DOI: 10.1128/mBio.00231-13
An international study, involving researchers from Griffith University’s Eskitis Institute, has discovered a molecule which could form the basis of powerful new anti-malaria drugs.
Professor Vicky Avery from Griffith University’s Eskitis Institute is co-author of the paper “Quinolone-3-Diarylethers: a new class of drugs for a new era of malaria eradication” which has been published in the journal Science Translational Medicine.
“The 4(1H)-quinolone-3- diarylethers are selective potent inhibitors of the parasite mitochondrial cytochrome bc1 complex,” Professor Avery said.
“These compounds are highly active against the types of malaria parasites which infect humans, Plasmodium falciparum and Plasmodium vivax,” she said.
“What is really exciting about this study is that a new class of drugs based on the 4(1H)- quinolone-3- diarylethers would target the malaria parasite at different stages of its lifecycle.”
This provides the potential to not only kill the parasite in people who are infected, thus treating the clinical symptoms of the disease, but also to reduce transmission rates.
“Just one of these properties would be of great benefit but to achieve both would really make a difference in reducing the disease burden on developing nations,” Professor Avery said.
“There is also the real possibility that we could begin to impact on the incidence and spread of malaria, bringing us closer to the ultimate goal of wiping out malaria altogether.”
The selected preclinical candidate compound, ELQ-300, has been demonstrated to be very effective at blocking transmission in the mouse models.
There is a further benefit in that the predicted dosage in patients would be very low and it’s expected that ELQ-300, which has a long half-life, would provide significant protection.
The development of a new chemical class of anti-malarial drugs is very timely as the parasite is becoming increasing resistant to currently available treatments.
Eskitis Director Professor Ronald J Quinn AM said “I congratulate Professor Avery on her contribution to the discovery of this new class of anti-malarials. This is an exciting discovery that closely aligns with the Institute’s focus on global health and fighting diseases that burden the developing world. We are continuing to take the fight to malaria along a number of fronts, including targeting its many life cycle stages.”
Journal reference: Science Translational Medicine
A. Nilsen, A. N. LaCrue, K. L. White, I. P. Forquer, R. M. Cross, J. Marfurt, M. W. Mather, M. J. Delves, D. M. Shackleford, F. E. Saenz, J. M. Morrisey, J. Steuten, T. Mutka, Y. Li, G. Wirjanata, E. Ryan, S. Duffy, J. X. Kelly, B. F. Sebayang, A.-M. Zeeman, R. Noviyanti, R. E. Sinden, C. H. Kocken, R. N. Price, V. M. Avery, I. Angulo-Barturen, M. B. Jiménez-Díaz, S. Ferrer, E. Herreros, L. M. Sanz, F.-J. Gamo, I. Bathurst, J. N. Burrows, P. Siegl, R. K. Guy, R. W. Winter, A. B. Vaidya, S. A. Charman, D. E. Kyle, R. Manetsch, M. K. Riscoe, Quinolone-3-Diarylethers: A New Class of Antimalarial Drug. Sci. Transl. Med. 5, 177ra37 (2013).
Provided by: Griffith University