A Major Step Forward for Dr. Éric Cohen's Laboratory
From left to right: Tram Pham and Eric Cohen
Although modern therapies now enable HIV carriers to survive, science has yet to decipher the deep mystery of how to eradicate this virus for good. On this note, new work from the laboratory of Dr. Éric Cohen, Director of the Human Retrovirology Unit at the Montréal Clinical Research Institute (IRCM) has taken an important step towards understanding the vulnerabilities of the virus's pockets of resistance in the body, with the hope of outsmarting them. This work is published in the journal iScience.
The Challenge of Latent Viruses in the Body
The presence of cells containing latent forms of HIV, which are not sensitive to current antiretroviral treatments, is an obstacle to the eradication of HIV in people living with the condition. In infected people on long-term treatment, eliminating these cells, known as reservoirs, would prevent, on one hand, the observed rebound of viremia and the progression of the disease when treatment is interrupted; on the other hand, it would prevent the chronic inflammation associated with the presence of these reservoirs, which leads to several co-morbidities (such as cognitive impairment, cardiovascular disease and certain cancers).
Understandably, eradicating these reservoirs remains an important objective in the long-term battle against HIV, a virus that has disrupted and claimed so many lives since its appearance in our societies, in the early 1980s.
In Depth
Dr. Cohen's laboratory work (achieved with the help of associate researcher Tram Pham), aimed to assess the impact of a family of molecules called ²SMAC Mimetic (SM)², which are used in the fight against cancer. SM has two important properties. First, it reactivates the expression of genes that respond to the transcription factor called NFkB, such as those of HIV, without causing important pro-inflammatory reactions. Second, it promotes death in cells that express high levels of inhibitors of apoptosis (a type of cell death), such as HIV reservoirs. Thus, the team focused on evaluating the effect of SM in a strategy known as ‘Shock and Kill’, which involves reactivating latent or dormant HIV in the reservoirs and killing the reactivated cells by sensitizing them to death by apoptosis.
In collaboration with Ascentage Pharma, the scientists tested APG-1387, a SMa currently used in oncology clinical trials. The evaluation was carried out in cell models and in vivo in the HIV latency model developed by this laboratory, in humanized mice, all with the aim of validating the concept.
Treatment with APG-1387 showed reductions of reservoirs’ size in infected mice treated with retroviral agents. Also, following the interruption of antiretroviral treatment, viremia rebound was reduced and appeared with some delay in APG-1387-treated mice, further suggesting a reduction in latent reservoirs.
“This work is important because it confirms that this strategy can work in vivo with little toxic effects; it also reveals vulnerabilities of virus reservoirs that could be exploited to eliminate latent HIV,” emphasizes Dr. Éric Cohen.
He adds that subsequent work will seek to combine this approach with interventions that stimulate the immune system to achieve greater elimination of virus reservoirs.
Acknowledgements
Dr. Éric Cohen's laboratory would like to warmly thank the organizations that helped fund and make this work possible, including CanCURE (Canadian Consortium for HIV Cure Research) supported by the Canadian Institutes of Health Research (CIHR), Ascentage Pharma and Dr. Élie Haddad's team (Azrieli Research Center, CHU Ste-Justine) for the humanized mouse models.
