Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers show how cells' DNA repair machinery can destroy viruses

22.01.2013
Studies suggest new approach to treating HIV

A team of researchers based at Johns Hopkins has decoded a system that makes certain types of immune cells impervious to HIV infection.


This is an illustration of what happens when viral DNA enters the nucleus of a cell with low dUTP levels (left) versus high dUTP levels (right).

Credit: Amy Weil

The system's two vital components are high levels of a molecule that becomes embedded in viral DNA like a code written in invisible ink, and an enzyme that, when it reads the code, switches from repairing the DNA to chopping it up into unusable pieces. The researchers, who report the find in the Jan. 21 early edition of the Proceedings of the National Academy of Sciences, say the discovery points toward a new approach to eradicating HIV from the body.

"For decades, we've seen conflicting reports on whether each of these components helped protect cells from viruses," says James Stivers, Ph.D., a professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine's Institute for Basic Biomedical Sciences. "By plotting how much of each are found in different types of cells, as well as the cells' response to HIV, we learned that both are needed to get the protective effect."

Researchers have long known that DNA's code is made up of four building blocks called nucleotides, commonly abbreviated A, T, G, and C. Before a cell divides, DNA-copying enzymes string these nucleotides together based on existing templates, so that each of the new cells gets its own copy of the genome. But because the T nucleotide, dTTP, is very similar to dUTP, a fifth nucleotide that doesn't belong in DNA, the copying enzyme sometimes mistakenly puts in a U where there should be a T.

To prevent this, says Stivers, most human cell types have an enzyme whose job is to break down dUTP, keeping its levels very low. Another quality control measure is the enzyme hUNG2, which snips stray Us out of newly copied DNA strands, leaving the resulting holes to be filled by a different repair enzyme. Certain immune cells called resting cells lack the first quality-control mechanism because, Stivers explains, "They're not replicating their DNA and dividing, so they couldn't care less if they have a lot of dUTP."

This is a critical piece of information, Stivers says, because when a retrovirus like HIV invades a cell, its first order of business is to make a DNA copy of its own genome, then insert that copy into the host cell's genome. If there are many dUTPs floating around in the cell, they will likely make their way into the new viral DNA, and, potentially, later be snipped out by hUNG2. The question, Stivers says, left open by the conflicting results of previous studies, was what effect, if any, this process has on HIV and other viruses.

To address this question, Amy Weil, a graduate student in Stivers' laboratory, measured dUTP levels and hUNG2 activity in a variety of human cells grown in the laboratory, then exposed them to HIV. Cells with high dUTP but little hUNG2 activity succumbed easily to the virus, which appeared to function just fine with a U-ridden genome. Similarly, cells with low dUTP levels but high hUNG2 activity were susceptible to HIV. For these cells, it seemed, hUNG2 would snip out the few stray Us, but the resulting holes would be repaired, leaving the viral DNA as good as new.

But in cells with both high dUTP and vigilant hUNG2, the repair process turned into a hack job, Stivers says, leaving the viral DNA so riddled with holes that it was beyond repair. "It's like dropping a nuclear bomb on the viral genome," he says.

By showing how dUTP and hUNG2 work together to protect resting cells from infection, Stivers says, the study identifies a new pathway that could restrict HIV infection in non-dividing cells. Current anti-retroviral drugs effectively suppress the virus, but, Stivers explains, they miss copies of the virus that hide out in non-dividing cells, and "the minute you stop taking anti-retrovirals, it starts replicating again." He suggests that drug strategies could be devised to target this pathway in affected cells, possibly lessening the pool of viruses hiding out in non-dividing cells. The principle could also be applied to other retroviruses, he says, since they, like HIV, all make DNA copies of their genomes as part of the infection process.

Other authors on the paper were Devlina Ghosh, Yan Zhou, Lauren Seiple and Robert F. Siliciano of the Johns Hopkins University School of Medicine; Moira A. McMahon of the University of California, San Diego; and Adam M. Spivak of the University of Utah School of Medicine.

The study was funded by the National Institute of General Medical Sciences (grant number GM056834) and the National Institute of Allergy and Infectious Diseases Extramural Activities (grant number AI081600).

Related Stories:

Before turning his attention to enzymes and nucleotides, James Stivers dealt in sharps and flats:

http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/about_us/
scientists/james_stivers.html
Finding That One-in-a-Billion That Could Lead to Disease:
http://www.hopkinsmedicine.org/news/media/releases/Finding_that_OneInABillion
_that_Could_Lead_to_Disease
The Hop and Slide of DNA Repair:
http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_
events/articles_and_stories/molecular_biology/201202_hop_and_slide_of_DNA
_repair

Shawna Williams | EurekAlert!
Further information:
http://www.jhmi.edu

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 >>>