Researchers in Montreal have made a breakthrough discovery in HIV research by finding a way to expel the virus from its hiding places and destroy it.
The elimination of these “reservoirs” is probably the last hurdle still to be overcome before we can hope to defeat the disease, but it’s a major challenge, warned Professor Eric Cohen, whose team at the Montréal Clinical Research Institute (IRCM) is behind this breakthrough.
“This is the new frontier in HIV research,” he said. “HIV is no longer a fatal disease, it’s a chronic disease that can be managed with lifelong treatment, but the new frontier is really about finding ways of eradicating the infection, of curing [infected people] so that they no longer have to take medication.”
Taking antiretroviral drugs allows people with HIV people to lead essentially normal lives, but only for as long as they take their medication regularly. If the medication is stopped, the virus comes out of hiding and the disease returns with a vengeance.
The presence of these reservoirs is also associated with chronic inflammation, leading to a number of comorbidities, such as cognitive impairment, cardiovascular problems and certain cancers.
To complicate matters further, researchers know that the cells in which HIV resides are highly resistant to cell death.
As a result, researchers have been trying for many years not only to find out where the virus is hiding, but above all to develop a strategy that would enable it to be eliminated once and for all.
“That’s what remains to be done,” Cohen said. “The decisive factor, I would say over the last 10 years, is that there have been cases of spontaneous recovery of people infected with HIV who had received a stem cell transplant for cancer. This shows that we can cure HIV if we can get rid of these reservoirs.”
Cohen’s laboratory set out to evaluate the efficacy of a family of molecules — the ²SMAC Mimetic (SM)² — which are used to combat cancer. The strategy consisted firstly of reactivating dormant HIV and then killing the reactivated cells by sensitizing them to a type of cell death known as “death by apoptosis.”
In collaboration with the company Ascentage Pharma, the scientists tested a molecule belonging to this family, APG-1387, which is currently being evaluated in clinical trials in oncology. In laboratory tests, treatment with APG-1387 showed a reduction in the size of reservoirs in mice infected and treated with retroviral agents.
In addition, following interruption of antiretroviral treatment, viremia rebound was reduced and appeared with a certain delay in mice treated with APG-1387, suggesting a reduction in latent reservoirs.
This is the “shock and kill” strategy, said Cohen.
“The cells in which [the virus] resides are completely invisible to the immune system,” he said. “So the idea is to use agents that are capable of reactivating the virus so that these cells become visible, and then to eliminate them using several strategies, immune or otherwise.”
The molecules used in this experiment kill two birds with one stone, added Professor Cohen: not only do they reactivate the virus, but they also make the infected cells more vulnerable.
For the moment, he added, the reduction in HIV reservoirs achieved is “detectable,” but it is not “sufficient” to eradicate the disease. If treatment is stopped, the viremia rebounds.
Subsequent work will therefore seek to combine this approach with interventions that stimulate the immune system in order to achieve a greater elimination of virus reservoirs, Cohen said.
The findings of the study were published by iScience.
This report by The Canadian Press was first published in French on Nov. 29, 2024.
