EU-funded research sheds light on 'shock-and-kill' strategy against HIV-1 Researchers in Italy have gained new insights into the so-called 'shock-and-kill' strategy, whereby latent HIV genes can be 'smoked out' of human cells. The results represent a significant step forward for researchers examining ways to eradicate HIV-1. The results of the prec... Researchers in Italy have gained new insights into the so-called 'shock-and-kill' strategy, whereby latent HIV genes can be 'smoked out' of human cells. The results represent a significant step forward for researchers examining ways to eradicate HIV-1. The results of the preclinical study, published in the journal Retrovirology, are an outcome of the EPITRON ('Epigenetic treatment of neoplastic disease') project, which was financed with EUR 1.1 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the EU's Sixth Framework Programme (FP6). The study was also financed in part by the Apo-Sys ('Apoptosis systems biology applied to cancer and AIDS: an integrated approach of experimental biology, data mining, mathematical modelling, biostatistics, systems engineering and molecular medicine') project, supported with EUR 11 million in funding under the Health Theme of the EU's Seventh Framework Programme (FP7). One of the major obstacles to eliminating the HIV-1 virus from patients is what researchers call the 'barrier of latency', involving latently infected, resting-memory white blood cells such as macrophages and T-cells (which direct other immune cells) that express the protein CD4. For example, a cell might harbour a dormant HIV genome that then becomes part of the organism; this means that the infection keeps coming back, even during antiretroviral therapy. To overcome the latency barrier, scientists have been looking into ways of activating HIV-1 to lure it to its death, a process called 'shock and kill'. The Italian research team used cell-line models to test several types of compounds that inhibit histone deacetylases (HDACs), enzymes that maintain HIV latency. HDAC inhibitors include, for example, valproic acid, which is also being investigated for its effects on neurodegenerative diseases. One problem the team faced was the fact that HDAC inhibitors only appear to have an effect on HIV when they are used in toxic doses. The researchers looked at 32 types of HDAC inhibitors belonging to a class that acts on a small group of enzymes (class I HDACs). They found that at non-toxic quantities, class I HDAC inhibitors could cause some of the latently infected cells to awaken. They repeated the experiment and added a drug that induces oxidative stress, called 'buthionine sulfoximine' (BSO). This drug enabled the class I HDAC inhibitors to act on more (but not all) of the latently infected cells. The 'awakened' infected cells were then snuffed out while the non-infected cells remained intact, despite being subjected to the combination of BSO and HDAC inhibitors. 'The combined effects of class-I-selective HDAC [inhibitors] and [...] BSO suggest the existence of an Achilles' heel that could be manipulated in order to facilitate the 'kill' phase of experimental HIV-1 eradication strategies,' the study reads. 'I really hope this study may open new avenues to the development of weapons able to eliminate the HIV-infected cells from the body,' said Dr Andrea Savarino, a retrovirologist at the Italian National Institute of Health. 'Such weapons, in combination with antiretroviral therapies, could hopefully allow people living with HIV/AIDS to get rid of the virus and return to a normal life.' While the results are promising, the researchers point out that the possible efficacy of the shock-and-kill approach remains a matter of debate. For example, they cite recent findings suggesting that 'there are different cellular reservoirs for HIV-1 latency and that each reservoir may require a specific activation strategy', and the fact that 'viral factors, along with cellular factors, may contribute to HIV-1 quiescence, and these factors may not be controlled by strategies using HDAC [inhibitors]'. Dr Savarino noted that testable drug combinations have been developed, composed of molecules that have passed phase I clinical trials for safety in humans. 'Although this type of approach is largely accepted by the scientific community, to be honest, we have to take into consideration that some scientists are sceptical about this approach, and others even think that a cure for HIV/AIDS will never be found. Experiments using animal models will shed a new light on this difficult problem,' he added. Countries Italy
