Nav: Home

Simulations describe HIV's 'diabolical delivery device'

June 15, 2016

From a virus's point of view, invading our cells is a matter of survival. The virus makes a living by highjacking cellular processes to produce more of the proteins that make it up.

From our point of view, the invasion can be a matter of survival too: surviving the virus. To combat viral diseases like HIV-AIDS, Ebola, and Zika, scientists need to understand the "life cycle" of the virus and design drugs to interrupt it. But seeing what virus proteins do inside living cells is extremely difficult, even with the most powerful imaging technologies.

Now University of Chicago scientists and their colleagues have developed an innovative computer model of HIV that gives real insight into how a virus "matures" and becomes infective. In doing so, it offers the prospect of help developing new anti-viral drugs and greatly extends what has been possible with computer simulations of biological systems. Their findings appeared in the May 13 edition of Nature Communications.

"Understanding the details of viral maturation is considered a holy grail," said Gregory Voth, UChicago's Haig P. Papazian Distinguished Service Professor in Chemistry, who built the model with research scientist John Grime. "It has a set of processes that are incredibly hard to stop. With our model, we've discovered a key set of dynamical steps in the maturation process. And we think we've identified two core aspects of HIV."

To mature and become infective, a virus must grow a little pear-shaped capsule called the capsid, which is made of proteins that wrap themselves around the RNA that will allow the virus to replicate. "This is the thing that's going to get shot into a new cell and release its contents," said Voth. "The capsid is like a little armor-plated container that carries with it the genetic material of the virus. And it is a diabolical delivery device."

Capsid growth details

Voth and Grime's model illuminates in detail how the capsid grows in HIV, something difficult to examine in real life because the capsid is tiny and surrounded by other material. "That's where computer simulations are so powerful," Voth said. "And in computer simulations you can turn things on and off, which you can't do in reality. It makes a huge difference in what you learn. It's not reality, but if the model's good it can be pretty darn close."

Voth and Grime worked with data and real-world images from experimental collaborators at the University of Virginia and the California Institute of Technology to make sure that their model was consistent with experimental findings. "Their important work helped us to build the model and validate it," Voth said.

After the HIV virus infects a cell it forms a "bud" on the cell's surface -- a virus particle that contains some cell membrane, proteins, and the virus's RNA. The bud breaks free of the cell as the "virion" and travels in the body. During that travelling period, critical proteins inside the bud are cut into bits by the enzyme HIV protease -- the target of many of today's anti-HIV drugs. Some 1,200 of these protein bits pair up and assemble themselves into the capsid, enclosing the RNA.

Conditions inside the virion are crowded. And that crowding turns out to be critical to whether a capsid can form or not. "With our simulations we can make it more and less crowded and you see a remarkable sensitivity to that," Voth said. Too little crowding, and the proteins are likely to speed past each other without interacting. Too much, and they grow useless bits and pieces.

But Voth and Grime found that even with a Goldilocks-like "just right" amount of crowding in their model, the capsid didn't grow properly. "We'd grow too much. Or we'd start growing multiple pieces of the shell and they wouldn't stick together in the right way, so you'd get a bunch of crazy-looking structures," Voth said. "We were fundamentally missing something."

Flipping and dancing

After a year of further work, they realized that before the protein bits pair up and add themselves to the growing capsid shell they are in constant motion, flipping and dancing around. For them to connect to each other and to the capsid they had to be oriented properly. This meant that only a few of them could participate in building the structure at any given time.

"We discovered that the contortions of these proteins are very important to limiting how fast these structures can grow, so it's just right," Voth said. "When we built that into the model, guided by published experimental data, that was the secret."

A large part of building a computer model is deciding what to leave out of it so that it is computationally tractable. "We develop methods to simplify the calculations while retaining their physical essence," said Voth. "And that opens up very broad frontiers of what can be studied that hasn't been possible before."

But even though it is simpler than what exists in nature, the HIV capsid model is tremendously complex. It took millions of hours of computer time on the National Science Foundation supercomputer Blue Waters in Urbana-Champaign to run the simulations.

"I don't think anyone's got close to simulating something of this complexity before," said Grime, who did most of the nuts and bolts construction. "I think it's a very significant advance in terms of what you can do with these sorts of models."

Voth envisions making similar models for other dangerous viruses, helping scientists discern the points in the cycle that might be good prospects for disruption by a drug.

"We could do this for Zika virus, for Ebola," he said. "Viruses have a capsid and that capsid contains their genetic material. So these sets of methodologies could be applied to any of them. We just need enough information and computer power."

University of Chicago

Related Hiv Articles:

Defective HIV proviruses reduce effective immune system response, interfere with HIV cure
A new study finds defective HIV proviruses, long thought to be harmless, produce viral proteins and distract the immune system from killing intact proviruses needed to reduce the HIV reservoir and cure HIV.
1 in 7 people living with HIV in the EU/EEA are not aware of their HIV status
Almost 30,000 newly diagnosed HIV infections were reported by the 31 European Union and European Economic Area (EU/EEA) countries in 2015, according to data published today by ECDC and the WHO Regional Office for Europe.
Smoking may shorten the lifespan of people living with HIV more than HIV itself
A new study led by researchers at Massachusetts General Hospital finds that cigarette smoking substantially reduces the lifespan of people living with HIV in the US, potentially even more than HIV itself.
For smokers with HIV, smoking may now be more harmful than HIV itself
HIV-positive individuals who smoke cigarettes may be more likely to die from smoking-related disease than the infection itself, according to a new study published in the Journal of Infectious Diseases.
Patients diagnosed late with HIV infection are more likely to transmit HIV to others
An estimated 1.2 million people live with HIV in the United States, with nearly 13 percent being unaware of their infection.
The Lancet HIV: New HIV infections stagnating at 2.5 million a year worldwide
A major new analysis from the Global Burden of Disease 2015 study, published today in The Lancet HIV journal, reveals that although deaths from HIV/AIDS have been steadily declining from a peak in 2005, 2.5 million people worldwide became newly infected with HIV in 2015, a number that hasn't changed substantially in the past 10 years.
NIH scientists discover that defective HIV DNA can encode HIV-related proteins
Investigators from the National Institutes of Health have discovered that cells from HIV-infected people whose virus is suppressed with treatment harbor defective HIV DNA that can nevertheless be transcribed into a template for producing HIV-related proteins.
Study examines risk of HIV transmission from condomless sex with virologically suppressed HIV infection
Among nearly 900 serodifferent (one partner is HIV-positive, one is HIV-negative) heterosexual and men who have sex with men couples in which the HIV-positive partner was using suppressive antiretroviral therapy and who reported condomless sex, during a median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission, according to a study appearing in the July 12 issue of JAMA, an HIV/AIDS theme issue.
HIV vaccine design should adapt as HIV virus mutates
Researchers from UAB, Emory and Microsoft demonstrate that HIV has evolved to be pre-adapted to the immune response, worsening clinical outcomes in newly infected patients.
Charlie Sheen's HIV disclosure may reinvigorate awareness, prevention of HIV
Actor Charlie Sheen's public disclosure in November 2015 that he has the human immunodeficiency virus (HIV) corresponded with the greatest number of HIV-related Google searches ever recorded in the United States, according to an article published online by JAMA Internal Medicine.

Related Hiv Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...