Scientists identify new therapeutic target for HIV

Scientists in Montreal and London have identified the key role played by the RORC2 transcription factor in HIV infection: the molecule attaches to parts of the virus genome without preventing it from replicating.

Co-led by researchers Petronela Ancuta from the Center de recherche hospitalier affiliated with the University of Montreal CRCHUM and Ariberto Fassati from University College London, the scientists today published their results in the journal PNAS.

When infected, HIV hides in immune cells called CD4 + T cells, which house it and allow it to continue to multiply.

Among CD4 + T cells, Th17 cells, responsible for defending and protecting the integrity of the mucous membranes, are particularly permissive in allowing the virus to replicate, thereby participating in its persistence.

Until now, there was no explanation for this phenomenon.

Our results show that RORC2, the molecule that regulates the immune function of Th17 cells, promotes virus expression within these cells by binding to a specific region of the viral genome. “

Petronela Ancuta, professor of medicine at UdeM

“In the laboratory, we have succeeded in inhibiting its action using small pharmacological molecules,” she explains. We were thus able to prevent the virus from replicating in CD4 + T cells of healthy participants. In the same cell type, this time from participants with HIV receiving antiretroviral therapy, we were successful in limiting viral spread. “

This proof of concept, completely new in this field of research, implies that the virus could even use RORC2 to ensure its survival in people living with HIV.

Doctoral student Tomas Raul Wiche Salinas, member of the Ancuta team, and postdoctoral researcher Yuwei Zhang, trained in the Ancuta laboratory, are the two co-first authors of the study. The CRCHUM research team also worked in close collaboration with that of Dr. Jean-Pierre Routy of the McGill University Health Center.

The first victims of HIV

In previous work, the Ancuta team has shown that Th17 cells represent one of the primary targets of HIV infection. In the battle of the immune system, these cells are among the first victims of HIV. Their loss creates a breach in the integrity of the intestinal mucous barrier and leads to systemic inflammation.

As for the surviving Th17 cells, they contribute to the persistence of the HIV reservoir by allowing the virus to replicate. This is called residual viral transcription – chronic inflammation leading to complications not directly related to AIDS – in patients treated with antivirals. Cardiovascular disease is one example of the possible complications.

“Our goal is to limit residual viral transcription in Th17 cells,” said Ancuta. “At present, our priority is to test the antiviral effects of RORC2 inhibitors in a preclinical model. “

To this end, the researcher’s team recently received a grant from the Canadian Institutes of Health Research totaling nearly $ 900,000 over four years. Ancuta, Fassati and Routy will be joined in their work by Eric Cohen from the Montreal Clinical Research Institute and by Elie Haddad from the CHU Ste-Justine pour enfants, affiliated to UdeM.

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