Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Random Gene Expression May Drive HIV into Hiding

29.07.2005


A single cell was infected with an HIV Tat model virus containing green fluorescent protein (GFP) and grown into a population of clones. The virus is integrated into a single identical genomic position in all cells, but the cells display highly variable levels of GFP, which are driven by random fluctuations in HIV-1 Tat protein.


Random fluctuations in gene expression can influence the fates of cells infected with human immunodeficiency virus (HIV) far more than previously thought, according to new research from Howard Hughes Medical Institute (HHMI) researchers at the University of California, Berkeley. By combining experimental and computational studies of HIV’s replication cycle, the researchers found evidence that the virus may become latent in some cells by harnessing the random molecular behavior of the cell.

HIV can hide in cells for years before reappearing to make new virus. Latency is considered one of the biggest reasons why drug therapy fails to eradicate HIV from patients. The new findings, which will be published in the July 29, 2005, issue of the journal Cell, could help scientists design new and more effective treatments to slow or halt the progression of HIV infection.

HIV normally replicates rapidly in the body’s white blood cells, but, in some cells, the virus stops replicating and becomes dormant. Researchers have long puzzled over how HIV makes the “decision” to become latent or to keep replicating in a certain cell.



“Most of the other groups studying the molecular mechanisms of HIV latency were coming at it from a deterministic point of view based on the belief that the system can only act in a predetermined way,” said lead author Leor Weinberger, who conducted the research as an HHMI predoctoral fellow in the laboratory of HHMI investigator Adam Arkin, in close collaboration with David Schaffer in the University of California, Berkeley, Department of Chemical Engineering. But the new results show that “any cell that gets infected can go down one of two paths,” Weinberger said.

Weinberger now is a postdoctoral fellow at Princeton University.

Inspired by work that Arkin had done in the 1990s, showing that random fluctuations in viral gene expression can influence latency in a bacterial virus, Weinberger wanted to see if the same process could be at work in HIV. No one had ever shown that this type of “noise” in gene expression could influence phenotype in infected mammalian cells, Weinberger said.

“I thought it was a cool idea,” he added, but “at the time, there wasn’t a lot of data to support it. It was pretty far out there.”

Weinberger, Arkin, and their colleagues created a model HIV-1 vector—a virus that could enter human cells, carrying with it a key component of HIV’s replication machinery: a gene called Tat. Tat facilitates transcription of HIV’s entire genome, including itself, which creates a positive-feedback loop: If a little bit of Tat is around, then the HIV genome is transcribed efficiently, which makes more Tat, and so on. If a cell has no Tat, then the HIV genome may remain untranscribed and unable to replicate, so the virus heads for latency.

When the scientists infected cultured human cells with their viral vector, they found that cells that initially expressed a low level of virus were very unstable: After a few days, all cells expressed either a high level of virus or none at all.

When Weinberger took one infected human cell with low levels of the virus and allowed it to proliferate into many genetically identical copies of itself, he found that these progeny did not all show the same behavior: some turned their viral expression on high and others turned it off.

This dichotomy in cell fate from genetically identical cells is consistent with the idea that random fluctuations in gene expression control what happens to the cells, the researchers said. To see if this really was the best explanation, they conducted a large array of experimental controls to discount other hypotheses and then created computer programs to model what would happen to the virus under different cellular conditions.

Of the 16 models they tested, only one produced results that matched those seen experimentally in the infected cells. In this model, after HIV’s RNA enters a host cell, it is copied into DNA, and then a little bit of Tat is made before the virus integrates into the host genome.

At this point, Tat must be chemically modified before it can encourage transcription of more HIV, and random thermal fluctuations in the cell can influence if and when these chemical modifications take place.

Because of Tat’s positive-feedback loop, “these fluctuations can be amplified and can lead to very different qualitative behaviors,” said Arkin.

If the appropriate modifications take place, then the HIV genome is transcribed and the positive feedback loop kicks in. If these Tat modifications don’t happen, then HIV ceases to be expressed, and the cell can then possibly enter a latent state.

The significance of fluctuations in expression are dependent on HIV being expressed at a low level in the cell initially, Arkin said. Commonly, it’s only when just a few molecules are interacting with each other that random fluctuations can have such a large effect on eventual outcome, he explained.

The researchers hope that understanding the molecular basis of HIV latency will lead to new treatments to slow or stop progression to AIDS. For example, Arkin suggested, the analysis implies that it might be effective to target the chemical modifications that Tat must undergo before it allows more HIV to be made. “When you quantify things and dissect them at this level, it gives you ways of exploring where your most vulnerable places might be.”

Commenting on the work in a preview article published in the same issue of Cell, William J. Blake and James J. Collins of the Center for Biodynamics of Boston University, wrote: “The work of Weinberger et. al. represents an important step in moving from studies that elucidate the origins of stochasticity in gene expression to those that investigate the consequences of such molecular noise on cellular function. The authors [present] a scenario in which HIV-1 can hedge its bets by having an inherent ability to proceed either to latency or viral production. This intriguing notion still needs to be tested experimentally, and more broadly, much work remains to be done to understand the functional role that gene expression noise potentially plays in the progression of disease.”

Jennifer Donovan | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>