Throughout antiretroviral therapy, HIV quietly hides in the CD4+ T lymphocyte reservoir. CD4+ T lymphocytes are a type of white blood cell that play a role in activating the immune system to fight infection.
The existence of these viral sanctuaries explains why antiretroviral therapy must be continued throughout a patient’s lifetime in order to prevent viral replication. According to the World Health Organization, more than 38 million people worldwide were living with HIV by the end of 2021.
In the journal Cell Reports, a research team led by Professor of Medicine Petronela Ancuta and her doctoral student Debashree Chatterjee showed for the first time that a protein called the aryl hydrocarbon receptor (AhR) plays a crucial role in the latency of this virus.
“In our study, we found that AhR, a transcription factor that regulates the expression of certain genes, has an antiviral effect on a patient’s CD4+ T cells,” Ancuta said. “To help HIV remain silent in reservoir cells, this molecule had an effect on the expression of HIC1, another transcription factor known to suppress HIV replication.”
To demonstrate this, the scientists knocked down the expression of AhR using the CRISPR/Cas9 system. They also used drugs that induce or block AhR activation. By neutralizing AhR activity by these two methods, the team observed viral growth occurring in CD4+ T cells from HIV-infected and antiretroviral-treated individuals.
Therefore, the study’s first authors, Ancuta and Chatterjee, and colleagues recommend the use of drugs that inhibit AhR activity as a “shock and kill” type of elimination strategy. Once reactivated in the presence of an AhR inhibitor (shock phase), HIV-infected cells are seen by the immune system and can be targeted and killed.
In certain types of cancerous tumors, the AhR pathway is activated by molecules from the environment, such as cigarette smoke, pollutants, or ligands from the gut microbiota and cellular metabolism. The resulting anti-inflammatory activity prevents an adequate antitumor immune response.
“Drugs that block AhR have been used against cancer in clinical trials,” said Ancuta, a researcher at the UdeM Teaching Hospital Research Center (CRCHUM). “In further research, we hope to test these inhibitors to see if we can eliminate HIV or substantially reduce the size of the viral reservoir in HIV-infected people who are taking antiretroviral therapy.”
To better understand the molecular mechanisms behind this viral latency, Ancuta will continue to collaborate with Carine Van Lint, an HIV transcriptionist at the Free University of Brussels, and Jean-Pierre Routy, professor of medicine at McGill University, to validate this new therapeutic target.
“Today, we have successfully demonstrated in patient cells how this AhR pathway is activated,” Ancuta said. “With the help of state-of-the-art technologies such as spatial transcriptomics, we hope to further characterize it specifically in the tissues of people living with HIV. This will allow us to validate this therapeutic target in the context of HIV.”