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.
Johns Hopkins Medicine: http://www.hopkinsmedicine.org
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Pigs ‘edited’ with a warthog gene to resist African swine fever could help spawn GM animal farms in the UK
Mouse House to make naturalist biopic, six years after box-office failure of Creation, starring Paul Bettany
International team spends 10 years making inroads into treatment of bacterium which kills up to half of those it infects
You may not know it, but you probably have some Neanderthal in you. For people around the world, except sub-Saharan Africans, about 1 to 3 percent of their DNA comes from Neanderthals, our close cousins who disappeared roughly 39,000 years ago.
Research at Yale plotted what happened in the brains of two scientists as they held a conversation
From medicines to jet fuel, we have so many reasons to celebrate the microbes we live with every day
Genome sequencing indicates Kennewick Man is Native American, reopening the bitter battle over whether he should be reburied or studied
In the article on the discovery of dinosaurs (They’re back, Review, 6 June) you state: “In Sussex, a local doctor uncovered fragmentary remains of what appeared to be two more species of colossal extinct land reptiles.” You grossly underplay the contribution of Lewes-born Gideon Mantell, geologist and palaeontologist, author and diarist, friend to princes and international scholars as well as local doctor. Mantell not only discovered (aided by his wife) the first remains of the iguanodon in 1824 but named it – as it resembled the tooth of an iguana. This was the first known land dinosaur, Mary Anning having identified the first sea-living dinosaur.Mantell went on to put together more pieces of the jigsaw with extra fossil discoveries. In contrast to Richard Owen, whose models form the basis for the Crystal Palace dinosaurs, Mantell stated correctly that iguanodon would have walked on their back legs, using their forearms to fight or gather food. He did, however, attribute the thumb spike to a nose horn though later corrected this assumption. The Natural History Museum has a display on Gideon and his wife Mary’s contribution as well as the large “Mantell-piece” of Iguanodon fossils that he had on show in his museum in Brighton. He sold it, along with many more priceless items, to the British Museum in 1838. Gideon Mantell’s reputation deserves better than your throwaway remark. Debby MatthewsLewes, East Sussex Continue reading...
Unique triangular hairs help keep Saharan silver ants cool at 70°C by manipulating the physics of light
Most animals wouldn't confront a fearsome predator like a lion. But through sophisticated group work, hyenas launch successful raids