Interfering with filovirus replication

Marburg virus, like its fellow filovirus Ebola virus, causes severe hemorrhagic fever with mortality rates reaching 90%. The Ebola virus outbreak currently sweeping western Africa has a mortality rate of 55–60%, according to the US Centers for Disease Control and Prevention. There are no approved treatments for viral hemorrhagic fever in humans; most infected individuals receive only supportive care. Now, scientists report a new strategy for treating Marburg virus using a tiny piece of RNA that interferes with its replication.

Scientists led by Thomas Geisbert at the University of Texas Medical Branch (Galveston) and Ian MacLachlan of Tekmira Pharmaceuticals (British Columbia, Canada) exposed 21 rhesus macaques to Marburg virus, then treated 16 of them with a lipid-encapsulated small interfering RNA at various intervals after infection: 30–45 minutes, 1 day, 2 days or 3 days. The untreated macaques died within 9 days, but all the treated monkeys survived the infection, regardless of when they received treatment (Sci. Transl. Med. 6, 250ra116; 2014).

This is the first report of a filovirus treatment that is successful when administered after viral infection is confirmed and clinical signs of disease are observed. The study's authors recommend that the treatment be further developed for potential use in humans. MH

A brain built from silk and rat neurons

The brain remains one of the least understood tissues in our body, in part because of its complexity. This complexity also makes it difficult to model the interactions of neuronal networks outside of a live organism.

Rather than reconstructing a whole-brain network, a team at Tufts University (Medford, MA) aimed to create a simple brain model by including only the most fundamental features relevant to neuronal interactions. The researchers constructed a scaffold made of silk protein fiber on which rat neurons were cultured in a collagen gel. Each scaffold was shaped like a donut, and these donuts were concentrically arranged to mimic the layers of the cortex, each containing compartmentalized grey matter and white matter regions (Proc. Natl. Acad. Sci. USA 10.1073/pnas.1324214111; published online 11 August 2014).

Because the brain-like model showed similar mechanical properties and electrical responses to rodent brains, the researchers, led by David Kaplan, thought that the model might be useful for studying traumatic brain injury. After dropping a weight on their silk 'brain,' they recorded its electrical responses and measured activity of glutamate. Both the pattern of neuronal activity and the changes in glutamate levels were similar to those seen in animal models of traumatic brain injury. KR

How fattened grizzly bears resist diabetes

In preparation for hibernation, grizzly bears (Ursus arctos horribilis) gain up to twice their body weight by accumulating fat. Yet they do not develop the insulin resistance and type 2 diabetes associated with obesity in humans and other species. To understand why, Lynn Nelson (Washington State University, Pullman) led a study of weight fluctuations and insulin sensitivity in six captive grizzly bears over the course of a year. The bears, which varied in age and sex, were studied before hibernation (in October), during hibernation (in January) and after hibernation (in May). The researchers found that the insulin responsiveness of grizzly bears varies seasonally, such that increased adiposity and insulin sensitivity occur during preparation for hibernation, followed by a period of insulin resistance during hibernation and a subsequent normalization of insulin sensitivity upon emergence from hibernation (Cell Metab. 20, 376–382; 2014).

The insulin sensitivity of the grizzly bears was found to be controlled by a protein called PTEN, which was inactivated in their fat cells during the fall, increasing sensitivity to insulin and allowing the bears to accumulate fat. The scientists suggest that this may be analogous to the state of 'healthy' obesity seen in humans with a genetic PTEN deficiency. KR

Marmosets uniquely suited for respiratory virus model

Middle East respiratory syndrome corona virus (MERS-CoV) is able to invade a cell after its spike protein binds to the cell-surface protein DPP4. Therefore, the interaction between the two proteins is an essential determinant of a species' susceptibility to MERS-CoV infection. In humans, the two proteins bind efficiently, making humans extremely susceptible to infection. In contrast, rodents, whose DPP4 is different from the human version, are resistant to the virus, and macaques, whose protein is similar but not identical to that of humans, develop a mild version of MERS-CoV infection. These variations have made it difficult to find suitable animal models for studying the virus.

Researchers at Rocky Mountain Laboratories (Hamilton, MT), a division of the US National Institute of Allergy and Infectious Diseases, took a rational approach to the problem, comparing DPP4 proteins of various species with human DPP4 at the relevant binding site. Common marmosets (Callithrix jacchus) were found to be an identical match (PLoS Pathog. 10, e1004250; 2014).

Next, the team, led by Heinz Feldmann and Vincent Munster, inoculated the marmosets with MERS-CoV, resulting in severe and, in two cases, lethal infections. The researchers wrote, “The development of the more severe marmoset model will ensure a better preclinical analysis of treatments.” KR

Xenon gas helps rats forget fear

Reconsolidation occurs when memories are recalled and re-encoded in the brain; during this process, the memories become temporarily susceptible to modification. Therefore, the reconsolidation process may provide a therapeutic window for post-traumatic stress disorder (PTSD) and other emotional memory disorders. Xenon gas can inhibit receptors that are involved in fear memory reconsolidation. Edward Meloni and colleagues (Harvard Medical School, Boston, MA) merged these two concepts into a study assessing the effects of xenon administration during the reconsolidation window. The results show that xenon can block fear memory reconsolidation, as evidenced by a reduction in the expression of fear-like behavior in rats in a conditioned fear model of PTSD.

In the fear-conditioning training, rats were placed in a specific cage, where they heard a specific tone and then received an electric shock. Rats were later returned to that cage and heard the same tone, and their responses during the next 2 minutes were monitored. Control rats spent 70% of that time immobile or 'frozen,' which is considered a fear-like behavior, but rats that were exposed to xenon first spent only 40% of that time frozen (PLoS ONE 9, e106189; 2014). “It was as though the animals no longer remembered to be afraid,” said Meloni in a press release. MH

Induce HIV to neutralize HIV

HIV can be effectively suppressed using antiretroviral therapy but surges back once therapy is stopped. Latent reservoirs of infected cells, invisible to the body's immune system and impervious to drugs, cause the infection to rebound if therapy is terminated.

Researchers at Rockefeller University (New York, NY) led by Michel Nussenzweig designed a new, two-part strategy to target latent viral reservoirs in the treatment of HIV infection. Their approach delivers broadly neutralizing antibodies against HIV along with a combination of viral transcription inducers. Inducing transcription activates the latent virus so that it is vulnerable to the antibody attack.

In a humanized mouse model of HIV, antibodies alone or with a single inducer were ineffective in preventing viral rebound. But combining antibodies with three inducers—each acting by different mechanisms—created a synergistic effect that decreased the latent reservoir. Almost 60% of mice treated with antibodies plus three inducers showed no viral rebound compared with only ∼10% of those treated with antibodies alone or in combination with a single inducer (Cell 158, 989–999; 2014). “This is the first time that any combination of agents has been found to prevent viral rebound in any animal model,” Nussenzweig said in a press release. MH