Eric Cohen et Tram Pham
Credit: IRCM
Modern therapies help people living with HIV to survive, but scientists are still trying to decipher the deep mystery of how to eventually eradicate the virus for good. Now new laboratory work in Canada sheds light on the vulnerabilities of HIV's pockets of resistance in the body, and potential ways to thwart them.
Led by of Université de Montréal medical professor Éric Cohen, director of the human retrovirology unit at the UdeM-affiliated Montreal Clinical Research Institute, the work is published in the journal iScience.
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 HIV. The elimination of these cells, known as reservoirs, would prevent the rebound of viremia observed in infected people who are on long-term treatment.
It would also prevent the progression of the disease when treatment is interrupted, as well as 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.
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 in the early 1980s.
In their lab, Cohen and associate researcher Tram Pham assessed 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 proinflammatory reactions. Second, it promotes death in cells that express high levels of inhibitors of apoptosis (a type of cell death), such as HIV reservoirs.
'Shock and kill'
Using a strategy known as 'shock and kill,' the researchers evaluated the effect of SM by reactivating latent, or dormant, HIV in the reservoirs, and killing the reactivated cells by sensitizing them to death by apoptosis.
In collaboration with the Chinese biopharmaceutical company Ascentage Pharma, the scientists tested APG-1387, a SMa now 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 a reduction in reservoir size in infected mice treated with retroviral agents. Also, following 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 in that it confirms that this strategy can work in vivo without too many toxic effects," Cohen said. "It also reveals vulnerabilities inherent in virus reservoirs that could be exploited to eliminate latent HIV."
He and his team will now seek to combine this approach with interventions that stimulate the immune system to achieve greater elimination of virus reservoirs.
About this study
"Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice," by Éric Cohen et al., was published Nov. 27, 2024 in iScience. Funding was provided by CanCURE (Canadian Consortium for HIV Cure Research), the Canadian Institutes of Health Research (CIHR), and Ascentage Pharma.
