Navigation Links
Researchers show how cells' DNA repair machinery can destroy viruses

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


Contact: Shawna Williams
Johns Hopkins Medicine

Related biology news :

1. Researchers turn one form of neuron into another in the brain
2. UGA researchers invent new material for warm-white LEDs
3. RUB researchers find over active enzyme in failing hearts
4. Researchers attack HIVs final defenses before drug-resistant mutations emerge
5. Researchers create flexible, nanoscale bed of nails for possible drug delivery
6. Researchers identify a new gene with a key role in obesity and diabetes
7. GW researchers find variation in foot strike patterns in predominantly barefoot runners
8. Joslin researchers identify important factor in fat storage and energy metabolism
9. UCSB researchers perform pioneering research on Type 2 diabetes
10. Researchers develop tool to evaluate genome sequencing method
11. Jackson Laboratory researchers provide definitive proof for receptors role in synapse development
Post Your Comments:
Related Image:
Researchers show how cells' DNA repair machinery can destroy viruses
(Date:6/2/2016)... , June 2, 2016 The Department ... has awarded the 44 million US Dollar project, for the ... Vehicle Plates including Personalization, Enrolment, and IT Infrastructure , ... in the production and implementation of Identity Management Solutions. Numerous ... however Decatur was selected for the ...
(Date:5/24/2016)... Ampronix facilitates superior patient care by providing unparalleled technology to leaders of the medical ... premium product recently added to the range of products distributed by Ampronix. ... ... ... Ampronix News ...
(Date:5/9/2016)... 2016 Elevay is currently known ... freedom for high net worth professionals seeking travel for ... connected world, there is still no substitute for a ... sealing your deal with a firm handshake. This is ... advantage of citizenship via investment programs like those offered ...
Breaking Biology News(10 mins):
(Date:6/24/2016)... TOKYO , June 24, 2016  Regular discussions on ... to take place between the two entities said Poloz. ... in Ottawa , he pointed to the ... and the federal government. ... Poloz said, "Both institutions have common economic goals, why not ...
(Date:6/24/2016)... ... June 24, 2016 , ... While the majority of commercial spectrophotometers and ... and the 6000i models are higher end machines that use the more unconventional z-dimension ... light beam from the bottom of the cuvette holder. , FireflySci has developed ...
(Date:6/23/2016)... ... June 23, 2016 , ... ... of its second eBook, “Clinical Trials Patient Recruitment and Retention Tips.” Partnering with ... in this eBook by providing practical tips, tools, and strategies for clinical researchers. ...
(Date:6/23/2016)... June 23, 2016   Boston Biomedical , ... compounds designed to target cancer stemness pathways, announced ... granted Orphan Drug Designation from the U.S. Food ... gastric cancer, including gastroesophageal junction (GEJ) cancer. Napabucasin ... to inhibit cancer stemness pathways by targeting STAT3, ...
Breaking Biology Technology: