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New HIV Cure Combination Drug Study
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"Part of the rationale behind our therapeutic strategy is based on the "shock and kill" effect exerted in vitro by the combination of auranofin and BSO on infected macrophages.......We administered buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis currently in clinical trials for cancer, in combination with auranofin to chronically SIVmac251-infected macaques under highly-intensified ART (H-iART). The ART/auranofin/BSO therapeutic protocol was followed, after therapy suspension, by a significant decrease of viral RNA and DNA in peripheral blood as compared to pre-therapy levels.....The enhanced immune response following treatment with auranofin/BSO is likely to be associated with restriction of the circulating pools of viral DNA following therapy suspension."
press release:
Drug-free remission of AIDS in monkeys: from anecdotal reports towards a globally scalable strategy.
Last week's reports of patients possibly "cured of AIDS" have fueled the hope for an end of this epidemics, although the strategy adopted cannot be scaled to the 33 million living with HIV/AIDS worldwide. However, another important step in this direction, that is the development of a scalable strategy able to induce a drug-free remission of AIDS in monkeys, is finally in the pipeline, researchers report in Retrovirology, one lead scientific journal in the field. Apart from rare cases of drug-free remission obtained treating very early with regular antiretroviral therapies, a cure for AIDS has been so far obtained only in Mr. Timothy Brown, i.e. the "Berlin patient", and, possibly, in two other recently reported cases in Boston. In all these patients, who also suffered from hematological malignancies, invasive and life-threatening techniques have been applied to remove the blood cells (including those harboring the virus) and replace them with new virus-free and cancer-free cells. Therefore, novel strategies are needed that be both safe and scalable to the 33 million people living with HIV/AIDS worldwide.
Now, by adding to antiretroviral therapy two existing drugs, i.e. the gold salt auranofin and the chemosensitizing agent buthionine sulfoximine (BSO), an Italian and American research team, led by Dr. Andrea Savarino at the Italian NIH (www.iss.it), observed, after therapy suspension, a drug-free remission of the disease in the macaque AIDS model (i.e. the animal model most closely resembling human AIDS). The drug combination safely and gradually replaced the "diseased" white blood cells with fresh and efficient cells, although, at first, it did not prevent the initial viral rebound after therapy suspension. "However", says Dr. Andrea Savarino, "during the subsequent follow up of the macaques, the new immune cells fought back the virus, rescuing the macaques to healthy conditions reminiscent of a drug-free remission of AIDS". "It's been the most exciting finding in my entire life", he concludes. "It turns out that a specific branch of the immune system is boosted by the addition of BSO to the drug cocktail, possibly mimicking an auto-vaccination against the virus", adds Iart Luca Shytaj, a collaborator of Dr. Savarino and first author of the article published in Retrovirology.
Dr. Savarino's team is planning to start a clinical trial early in 2014.The location and timing of the clinical trial will be announced at the biannual conference on "HIV persistence during therapy" to be held in Miami next December and bringing together the world's top experts in the field.
http://www.retrovirology.com/content/10/1/71
http://www.retrovirology.com/content/10/1/71/abstract
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Investigational treatment suspension and enhanced cell-mediated immunity at rebound followed by drug-free remission of simian AIDS
Iart Luca Shytaj, Barbara Chirullo, Wendeline Wagner, Maria G Ferrari, Rossella Sgarbanti, Alessandro Della Corte, Celia LaBranche, Lucia Lopalco, Anna Teresa Palamara, David Montefiori, Mark G Lewis, Enrico Garaci and Andrea Savarino
Retrovirology 2013, 10:71 doi:10.1186/1742-4690-10-71
Published: 16 July 2013
Abstract (provisional)
Background
HIV infection persists despite antiretroviral treatment (ART) and is reignited as soon as therapies are suspended. This vicious cycle is fueled by the persistence of viral reservoirs that are invulnerable to standard ART protocols, and thus therapeutic agents able to target these reservoirs are needed. One such agent, auranofin, has recently been shown to decrease the memory T-cell reservoir in chronically SIVmac251-infected macaques. Moreover, auranofin could synergize with a fully suppressive ART protocol and induce a drug-free post-therapy containment of viremia.
Results
We administered buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis currently in clinical trials for cancer, in combination with auranofin to chronically SIVmac251-infected macaques under highly-intensified ART (H-iART). The ART/auranofin/BSO therapeutic protocol was followed, after therapy suspension, by a significant decrease of viral RNA and DNA in peripheral blood as compared to pre-therapy levels. Drug-free post-therapy control of the infection was achieved in animals with pre-therapy viral loads ranging from values comparable to average human set points to levels largely higher. This control was dependent on the presence CD8+ cells and associated with enhanced levels of cell-mediated immune responses.
Conclusions
The level of post-therapy viral set point reduction achieved in this study is the largest reported so far in chronically SIVmac251-infected macaques and may represent a promising strategy to improve over the current "ART for life" plight.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
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