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The East African : January 6th 2014
28 The EastAfrican OUTLOOK JANUARY 4-10,2014 S CI E N C E Studies detail how white blood cells ‘commit mass suicide’ to fight HIV The fiery deaths attract more cells to come over and help, initiating a domino effect of immune system By MEERI KIM New York Times News Service I n a last-ditch effort to rid the body of HIV, droves of white blood cells self-destruct in an explosive mass suicide that drives the progression toward Aids, a pair of new studies has found. These fiery deaths attract more unsuspecting cells to come over and help, initiating a domino effect of immune system destruction. The discovery of these mechanisms of cell death has solved a decades-long mystery that has plagued HIV researchers since the disease emerged. And researchers claim that an existing drug may be able to halt this suicide cascade in its tracks. One study, in Nature, identifies the chain reaction and corresponding enzymes involved. The other, from Science, pinpoints a protein within the white blood cell that sniffs out the viral DNA and tells the cell to pull the trigger on itself. Both were published online early December. “For 30 years, we thought it was directly the virus killing the cell,” said immunologist Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, who was not involved in the studies. “This wasn’t a particularly satisfying explanation, since many more cells die than were infected.” Both findings come from the laboratory of immunologist Warner Greene of the Gladstone Institutes, a biomedical research non-profit organisation in California. Resting cells HIV most often targets a type of white blood cell, called the CD4 T-cell. The virus latches onto some of these cells and inserts its own genetic material inside. Some of these T-cells become virus-replicating units, but other cells resist and become bystanders, called resting cells. Scientists have speculated that the virus-producing infected cells become so full of the virus they were producing that they die. Or they realise something was very wrong, and perform a clean, programmed cell death, called apoptosis. The deaths of these CD4 T-cells are offset by the body producing more of them in response. But after a while, the body cannot keep up, and the T-cell count drops, leading to the onset of Aids. Then, diseases that used to be easy to fend off take over. Double stranded DNA CD4 receptor and coreceptor HIV ENTRY TO T CELL Docking Fusion Lifesaving hepatitis C d≥ug app≥oved By A SPECIAL CORRESPONDENT IRIN FOLLOWING APPROVALS in the US and Europe of a new drug to treat hepatitis C, activists are pushing for the medication to be made available in poor countries, a development reminiscent of the activism that forced down HIV/ Aids drug prices a decade ago in Brazil, South Africa and Thailand. The World Health Organisation Viral RNA Reverse Transcription cDNA Cromosomal DNA (WHO) estimates that as many as 185 million people are infected with hepatitis C, which is often called a “viral time bomb” because it can exist, undiagnosed, in a person’s body for many years without causing symptoms. According to the Open Society Intergarion Foundations (OSF), more than 350,000 people die every year from liver disease related to the virus, and every year an estimated three to four million more people are infected. Many of these people are co-infected with HIV. The illnesses are both blood-borne and have shared routes of transmission, particularly injecting drug use. Provirus “It’s a race be- tween production and destruction,” Fauci said. Greene and his colleagues discovered that 95 per cent of the dying T-cells were resting cells. These cells have the virus DNA in them, but unlike the cells that become virus-replicating units, the resting cells initiate a self-destruct mechanism that is downright gruesome, called pyroptosis. It causes cell swelling, membrane rupture and leaky insides. “It is much more a cellular suicide than a viral murder,” Greene said. “The cells are committing suicide in a vain attempt to kill the virus.” Because of its explosive and messy nature, pyroptosis is a good way to signal to the troops to clean up. But inflammation of these cells in death causes the new cells to fall to the same grim fate. “This process just becomes a gristmill for chewing up CD4 cells,” Greene said. His team took four years to gather all the results. First, they inserted a fluorescent dye into the virus so they could identify which cells harboured HIV-replicating units. Then they waited to see which cells died. To their shock, the vast majority of cell death was among the resting, non-virus-replicating cells. From there, they wanted to find it triggers a series of responses in the cell, including the work of an enzyme pase-1 that mediates osis. The drug blocks me. actually on the shelf, disease,” said Greene, g to develop a clinical of the drug in HIV/ s. “We tested that drug -culture systems, and utifully.” from the antiretrovi- the molecule that was the pyroptosis instigator. The team analysed the DNA of the resting CD4 T-cells using a technique called mass spectroscopy to find every protein that was bound to it. From the original laundry list of proteins, they picked the most likely candidates and progressively knocked out each one in newly made T-cells to tease out what each protein did. When they knocked out one in particular, IFI16, the cells no longer selfdestructed. “IFI16 is like the trigger, and the pyroptosis is like the gun,” he said. “IFI16 initiates the response.” Greene and his colleagues also de- scribe a drug — one already cleared for human use, originally developed to prevent seizures — that could potentially prevent pyroptosis. After IFI16 recognises the virus DNA, rals currently used for HIV/Aids in that it would target the host rather than the virus. But Fauci does not believe that it will be a replacement for antiretrovirals, but instead that they could possibly be used together as a joint treatment. Greene saw his first Aids case in 1981 — the year the disease was identified — while working at the National Institutes of Health. At the time, he was conducting research on a different human retrovirus but found himself fascinated by the ever-unfolding mysteries of HIV. “Every step of the way in this field of work, I have been absolutely amazed,” he said. “Each lab meeting is thrilling.” Washington Post-Bloomberg Researcher studying the banded DNA sequences of a hepatitis virus. Picture: AFP Unaffordable Unlike HIV, hepatitis C can be cured. But current treatment options have serious side effects, do not always work and are unaffordable for most people. The existing treatment, pegylated interferon, which is manufactured by Roche and Merck, can cost as much as $18,000 for a 48-week course. Interferon, which must be in- jected, can, in combination with the drug ribavirin, cure 40-70 percent of patients who use it. But its high cost has kept it out of reach for most patients, except in Egypt and Thailand, where the governments were able to negotiate significant price reductions with drug manufacturers.
December 30th 2013
January 13th 2014