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.
Sleep is a critical period for memory consolidation, and most people don’t get enough. Research has shown that even brief periods of sleep deprivation can lead to deficits in memory formation.
In a new study, published in the Journal of Neuroscience, a team led by scientists from the University of Pennsylvania found that a particular set of cells in a small region of the brain are responsible for memory problems after sleep loss. By selectively increasing levels of a signaling molecule in these cells, the researchers prevented mice from having memory deficits.
Robbert Havekes was the lead author on the study. He is a research associate in the lab of Ted Abel, the study’s senior author and Brush Family Professor of Biology in Penn’s School of Arts & Sciences. Coauthors from the Abel lab included Jennifer C. Tudor and Sarah L. Ferri. They collaborated with Arnd Baumann of Forschungszentrum Jülich, Germany, and Vibeke M. Bruinenberg and Peter Meerlo of the University of Groningen, The Netherlands.
In 2009, a group from Abel’s lab published a study in Nature that identified the cyclic AMP, or cAMP, signaling pathway as playing a role in sleep-loss-associated memory problems. Whereas depriving mice of sleep impaired their spatial memory, restoring levels of cAMP in their brain prevented this effect.
“The challenge following this important study,” Abel said, “was to determine if the impact of sleep deprivation was mediated by particular regions of the brain and particular neural circuits. We suspected that the hippocampus, the brain region that mediates spatial navigation and contextual memory, was critical.”
In the current work, they set out to answer these questions. They targeted excitatory neurons because of their importance in transmitting signals in the brain and the fact that their functioning relies on cAMP signaling. The limitation of previous studies was that they lacked a way to increase cAMP in just one area of the brain in a cell-type specific fashion. Havekes, Abel and colleagues devised a way of doing this that they term a “pharmacogenetic” approach, blending genetic modification and drug administration.
They engineered a non-pathogenic virus to harbor the gene encoding the receptor for the protein octopamine, which triggers cAMP pathway activation in fruit flies but is not naturally found in the brains of mice. The researchers injected this virus into the hippocampus of mice so that the excitatory neurons in that region alone would express the octopamine receptor.
“It sounds weird. Why would you put a receptor there that is never going to be activated?” Havekes said. “The trick is, you follow that up by giving mice the ligand of the receptor, which is octopamine, and that will activate the receptors only where they are present.”
The team confirmed that only the excitatory hippocampal neurons expressed the receptor and that they could selectively increase cAMP levels in only these cells by giving the mice a systemic injection of octopamine.
“This way, we could manipulate the cAMP pathways that we previously saw being affected by sleep deprivation but selectively in specific neural circuits in the brain,” Havekes says.
With this pharmacogenetic tool in hand, Havekes, Abel and colleagues began the sleep deprivation tests with the mice expressing the octopamine receptor in their hippocampus. First the researchers trained mice in a spatial memory task. They put them in a box that had three different objects, each in a distinct location.
Then, because previous research had shown that cAMP signaling contributes to hippocampus-dependent memory consolidation in two time windows—first directly after training and again three to four hours after training—the researchers gave mice in the experimental groups injections of octopamine in both of these windows to boost cAMP levels.
Mice receiving the cAMP boost were divided into two groups: One was left to sleep undisturbed, while the other was sleep-deprived for five hours by gently tapping their cage or rearranging their bedding.
One full day after the initial training, all of the mice were tested again. This time, there was a twist: one of the objects originally in the box had been moved to a new location.
“If the mice had learned and remembered the location of the objects during their training, then they would realize, okay, this is the object that has moved, and they’ll spend more time exploring that particular object,” Havekes explained. “If they didn’t remember well, they would explore all the objects in a random fashion.”
The researchers found that the sleep-deprived mice that received the octopamine injections spent more time exploring the object that had moved, just as mice that had not been sleep deprived did. On the other hand, sleep-deprived mice that didn’t express the receptor explored all the objects at random, a sign that they had failed to remember the locations of the objects from their initial training as a result of the brief period of sleep deprivation.
“What we’ve shown is this memory loss due to sleep deprivation is really dependent on misregulation of cAMP signaling in the excitatory neurons of the hippocampus,” Havekes said.
As a next step, the group would like to explore what cAMP is doing to help consolidate memory. They would also like to investigate how other cell types in the brain, such as astrocytes, might be affected. And finally, while this study focused on the impact of a brief period of sleep deprivation, Havekes is curious to know how not getting enough sleep on a daily basis, as is more similar to human experiences, might be affecting memory.
“Thinking about people who do shift work or doctors who work long hours, if we can tackle the cognitive problems that result from sleep loss, that would be a great thing,” Havekes said.
“At least in the mouse using these sophisticated tools, we’re able to reverse the negative impact of sleep deprivation on cognition,” Abel said.
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.”
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
Northwestern Medicine scientists have identified a component of the herpesvirus that “hijacks” machinery inside human cells, allowing the virus to rapidly and successfully invade the nervous system upon initial exposure.
Led by Gregory Smith, associate professor in immunology and microbiology at Northwestern University Feinberg School of Medicine, researchers found that viral protein 1-2, or VP1/2, allows the herpesvirus to interact with cellular motors, known as dynein. Once the protein has overtaken this motor, the virus can speed along intercellular highways, or microtubules, to move unobstructed from the tips of nerves in skin to the nuclei of neurons within the nervous system.
This is the first time researchers have shown a viral protein directly engaging and subverting the cellular motor; most other viruses passively hitch a ride into the nervous system.
“This protein not only grabs the wheel, it steps on the gas,” says Smith. “Overtaking the cellular motor to invade the nervous system is a complicated accomplishment that most viruses are incapable of achieving. Yet the herpesvirus uses one protein, no others required, to transport its genetic information over long distances without stopping.”
Herpesvirus is widespread in humans and affects more than 90 percent of adults in the United States. It is associated with several types of recurring diseases, including cold sores, genital herpes, chicken pox, and shingles. The virus can live dormant in humans for a lifetime, and most infected people do not know they are disease carriers. The virus can occasionally turn deadly, resulting in encephalitis in some.
Until now, scientists knew that herpesviruses travel quickly to reach neurons located deep inside the body, but the mechanism by which they advance remained a mystery.
Smith’s team conducted a variety of experiments with VP1/2 to demonstrate its important role in transporting the virus, including artificial activation and genetic mutation of the protein. The team studied the herpesvirus in animals, and also in human and animal cells in culture under high-resolution microscopy. In one experiment, scientists mutated the virus with a slower form of the protein dyed red, and raced it against a healthy virus dyed green. They observed that the healthy virus outran the mutated version down nerves to the neuron body to insert DNA and establish infection.
“Remarkably, this viral protein can be artificially activated, and in these conditions it zips around within cells in the absence of any virus. It is striking to watch,” Smith says.
He says that understanding how the viruses move within people, especially from the skin to the nervous system, can help better prevent the virus from spreading.
Additionally, Smith says, “By learning how the virus infects our nervous system, we can mimic this process to treat unrelated neurologic diseases. Even now, laboratories are working on how to use herpesviruses to deliver genes into the nervous system and kill cancer cells.”
Smith’s team will next work to better understand how the protein functions. He notes that many researchers use viruses to learn how neurons are connected to the brain.
“Some of our mutants will advance brain mapping studies by resolving these connections more clearly than was previously possible,” he says.
Sofia V. Zaichick, Kevin P. Bohannon, Ami Hughes, Patricia J. Sollars, Gary E. Pickard, Gregory A. Smith. The Herpesvirus VP1/2 Protein Is an Effector of Dynein-Mediated Capsid Transport and Neuroinvasion. Cell Host & Microbe, 2013; 13 (2): 193 DOI: 10.1016/j.chom.2013.01.009