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HIV-infected cells made to self-destruct

发布时间:2019-03-02 05:20:00来源:未知点击:

By Shaoni Bhattacharya Targeting a protein which helps repair DNA damage in human cells could provide a new way of fighting HIV infection, new research suggests. Crucially, harnessing this approach might offer a way of combating multi-drug resistant strains of HIV which are becoming increasingly common. Most HIV drugs work by targeting proteins produced by the HIV virus itself. But because HIV has a short life-cycle and readily mutates, the proteins it produces quickly evolve to become resistant to these antiretroviral drugs. Now, a new “proof of concept” study shows that blocking one of the key cellular proteins which regulates a cell’s response to DNA damage can stop HIV hijacking it and using it to manufacture thousands more copies of itself. Inhibiting the protein – called ataxia-telangiectasia-mutated (ATM) – in human cells exposed to HIV in the lab stopped the virus from splicing itself into many of the exposed cells’ DNA and instead triggered their demise. “By targeting ATM we are stopping the infected cell from producing more virus,” says Mark O’Connor, project leader and head of biology at Kudos Pharmaceuticals Limited in Cambridge, UK. “The most exciting thing is the study demonstrates the proof of concept that targeting a cellular factor required for HIV replication, but not itself essential to the cell, allows you to overcome the problem of drug resistant HIV.” ATM is a “non-essential” protein which detects breaks in the normally double-stranded DNA in a mammalian cell’s nucleus. This break might occur due to damage caused by ionising radiation, for example. If ATM detects a DNA break it stimulates a repair mechanism. When HIV infects a cell, it cleaves the host’s DNA to integrate itself in the genome. This DNA break is detected by ATM, which then kick starts the appropriate mechanisms to repair the cut – allowing HIV to settle successfully into the host’s genome. The researchers suspected that if the break was left unchecked it would invoke a DNA damage response, resulting in the death of the cell – so HIV could not replicate and spread. To inhibit ATM, the team used a molecule called KU-55933, identified by screening a library of potential compounds. And it did indeed suppress the replication of HIV-1 in human T-lymphocyte cells and increased cell death. It also performed favourably compared to established antiretroviral drugs like lamivudine and abacavir. And where much higher doses of these two drugs are needed to inhibit drug-resistant HIV, KU-55933 showed similar efficacy against all of the HIV strains tested. But O’Connor warns that although this approach has worked in the lab it may not necessarily translate to the clinic. “Obviously, whenever you target a cellular factor you are always aware of the potential for side-effects,” he told New Scientist. Although ATM is not essential, total absence causes a rare human genetic disease where patients live only into their twenties or thirties. He says the inhibition of ATM is different from a complete loss but that safety and efficacy studies will need to be carried out in animals before the approach can move forward – his team are currently looking for industry partners. A potentially safer method might be to give a drug based on this approach intermittently alongside other drugs, he suggests. “This sounds like an exciting development – but we will have to wait and see how the research develops,” says a spokesperson for the UK charity, the Terrence Higgins Trust. “To have an effective treatment against multi-drug-resistant strains of HIV would be a huge advantage, but these are still early days and in the meantime it is important to stress that condoms are the only effective means of preventing HIV.” More on these topics: