Blocking Zika: New antiviral may treat and prevent infection, a Stanford study suggests

Image of the surface of the Zika virus by Purdue University/courtesy of Kuhn and Rossmann research groups

The Zika virus, which made headlines in 2016 following an outbreak in South America, is transmitted by mosquitos and can cause serious birth defects and neurological problems. Researchers are searching for antiviral treatments or effective vaccines to address this global health threat, but there are currently no approved treatments.

Now, Stanford researchers are taking a different approach — investigating cellular factors of humans that are essential for Zika to propagate. One of those factors is a type of protein called Hsp70, which helps proteins fold correctly and performs a wide range of housekeeping and quality-control functions in cells.

Based on a series of experiments in mosquito and human cells, the Stanford study found that certain Hsp70 proteins are required in multiple steps of the Zika virus’ lifecycle. By blocking Hsp70 with an Hsp70 inhibitor drug, the researchers were able to prevent virus replication, as recently reported in Cell Reports.

One advantage of targeting the human host protein to thwart Zika is that it is less likely to promote drug resistance, Judith Frydman, PhD, senior author of the paper and a professor of genetics and of biology at Stanford, told me.

“The emergence of drug-resistant variants is a major obstacle for the development of antiviral therapies,” she continued. “We hypothesize that because Hsp70 is required for several different steps in the Zika virus cycle, it would be difficult for Zika to acquire enough mutations to develop resistance to the Hsp70 inhibitors. This opens the way to both therapeutic and prophylactic use of these drugs for short courses of treatment without losing effectiveness due to resistance.”

In addition, the team found that the Hsp70 inhibitors showed negligible toxicity to the host cells at the concentrations needed to fully block virus production. They demonstrated this lack of toxicity in both human cells and mice.

“The virus has a much higher demand for Hsp70 than the host cellular processes,” Frydman said. “We can exploit the viral ‘addiction’ to Hsp70 for treatment to prevent the virus from producing the proteins it needs to replicate and infect cells. But most importantly, we show Hsp70 inhibitors can be administered to animals at therapeutically effective doses. To my knowledge, this is the first drug that actually works for Zika-infected animals, protecting them from lethal infection and disease symptoms.”

The researchers believe their new approach could serve to create broad-spectrum antivirals that work against other existing and emerging viruses. In fact, this class of drugs could also treat other insect-borne viruses including Dengue virus and Yellow Fever, Frydman said.

“Our findings provide new strategies to develop a novel class of antivirals that will not be rendered ineffective by the emergence of drug resistance,” Frydman said. “This unique property of targeting host factors used for viral protein folding therapeutically may close a fundamental gap in antiviral drug development.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.


Shedding New Light on Luminous Blue Variable Stars: 3D Simulations Disperse Some of the Mystery Surrounding Massive Stars

A snapshot from a simulation of the churning gas that blankets a star 80 times the sun’s mass. Intense light from the star’s core pushes against helium-rich pockets in the star’s exterior, launching material outward in spectacular geyser-like eruptions. The solid colors denote radiation intensity, with bluer colors representing regions of larger intensity. The translucent purplish colors represent the gas density, with lighter colors denoting denser regions. Image: Joseph Insley, Argonne Leadership Computing Facility.

Three-dimensional (3D) simulations run at two of the U.S. Department of Energy’s national laboratory supercomputing facilities and the National Aeronautics and Space Administration (NASA) have provided new insights into the behavior of a unique class of celestial bodies known as luminous blue variables (LBVs) — rare, massive stars that can shine up to a million times brighter than the Sun.

Astrophysicists are intrigued by LBVs because their luminosity and size dramatically fluctuate on a timescale of months. They also periodically undergo giant eruptions, violently ejecting gaseous material into space. Although scientists have long observed the variability of LBVs, the physical processes causing their behavior are still largely unknown. According to Yan-Fei Jiang, an astrophysicist at UC Santa Barbara’s Kavli Institute for Theoretical Physics, the traditional one-dimensional (1D) models of star structure are inadequate for LBVs.

“This special class of massive stars cycles between two phases: a quiescent phase when they’re not doing anything interesting, and an outburst phase when they suddenly become bigger and brighter and then eject their outer envelope,” said Jiang. “People have been seeing this for years, but 1D, spherically-symmetric models can’t determine what is going on in this complex situation.”

Instead, Jiang is leading an effort to run first-principles, 3D simulations to understand the physics behind LBV outbursts — using large-scale computing facilities provided by Lawrence Berkeley National Laboratory’s National Energy Research Scientific Computing Center (NERSC), the Argonne Leadership Computing Facility (ALCF), and NASA. NERSC and ALCF are DOE Office of Science User Facilities.

Physics Revealed by 3D

In a study published in Nature, Jiang and his colleagues from UC Santa Barbara, UC Berkeley, and Princeton University ran three 3D simulations to study three different LBV configurations. All the simulations included convection, the action when a warm gas or liquid rises while its cold counterpart sinks. For instance, convection causes hot water at the bottom of a pot on a stove to rise up to the top surface. It also causes gas from a star’s hot core to push to its outer layers.

During the outburst phase, the new 3D simulations predict that convection causes a massive star’s radius to irregularly oscillate and its brightness to vary by 10 to 30 percent on a timescale of just a few days — in agreement with current observations.

“Convection causes the star to expand significantly to a much larger size than predicted by our 1D model without convection. As the star expands, its outer layers become cooler and more opaque,” Jiang said.

Opacity describes how a gas interacts with photons. The researchers discovered that the helium opacity in the star’s outer envelope doubles during the outburst phase, making it more difficult for photons to escape. This leads the star to reach an effective temperature of about 9,000 degrees Kelvin (16,000 degrees Fahrenheit) and triggers the ejection of mass.

“The radiation force is basically a product of the opacity and the fixed luminosity coming from the star’s core. When the helium opacity doubles, this increases the radiation force that is pushing material out until it overcomes the gravitational force that is pulling the material in,” said Jiang. “The star then generates a strong stellar wind, blowing away its outer envelope.”

Massive Simulations Required

Massive stars require massive and expensive 3D simulations, according to Jiang. So he and his colleagues needed all the computing resources available to them, including about 15 million CPU hours at NERSC, 60 million CPU hours at ALCF, and 10 million CPU hours at NASA. In addition, NERSC played a special role in the project.

“The Cori supercomputer at NERSC was essential to us in the beginning because it is very flexible,” Jiang said. “We did all of the earlier exploration at NERSC, figuring out the right parameters to use and submissions to do. We also got a lot of support from the NERSC team to speed up our input/output and solve problems.”

In addition to spending about 5 million CPU hours at NERSC on the early phase of the project, Jiang’s team used another 10 million CPU hours running part of the 3D simulations.

“We used NERSC to run half of one of the 3D simulations described in the Nature paper and the other half was run at NASA. Our other two simulations were run at Argonne, which has very different machines,” said Jiang. “These are quite expensive simulations, because even half a run takes a lot of time.”

Even so, Jiang believes that 3D simulations are worth the expense because illuminating the fundamental processes behind LBV outbursts is critical to many areas of astrophysics — including understanding the evolution of these massive stars that become black holes when they die, as well as understanding how their stellar winds and supernova explosions affect galaxies.

Jiang also used NERSC for earlier studies, and his collaboration is already running follow-up 3D simulations based on their latest results. These new simulations incorporate additional parameters — including the LBV star’s rotation and metallicity — varying the value of one of these parameters per run. For example, the speed from rotation is larger at the star’s equator than at its poles. The same is true on Earth, which is one of the reasons NASA launches rockets from Florida and California near the equator.

“A massive star has a strong rotation, which is very different at the poles and the equator. So rotation is expected to affect the symmetry of the mass loss rate,” said Jiang.

The team is also exploring metallicity, which in astrophysics refers to any element heavier than helium.

“Metallicity is important because it affects opacity. In our previous simulations, we assumed a constant metallicity, but massive stars can have very different metallicities,” said Jiang. “So we need to explore the parameter space to see how the structure of the stars change with metallicity. We’re currently running a simulation with one metallicity at NERSC, another at Argonne, and a third at NASA. Each set of calculations will take about three months to run.”

Meanwhile, Jiang and his colleagues already have new 2018 data to analyze. And they have a lot more simulations planned due to their recent allocation awards from INCITE, NERSC, and NASA.

“We need to do a lot more simulations to understand the physics of these special massive stars, and I think NERSC will be very helpful for this purpose,” he said.

This is a reposting of my news feature originally published by Berkeley Lab’s Computing Sciences.