An international team led by two Université de Montréal researchers unveiled how a molecule capable of opening the "shell" of HIV, improves the elimination of infected cells.
In a study published in Nature Communications, Jonathan Richard and Andrés Finzi demonstrate how a new CD4-mimetic compound, CJF-III-288, modifies the HIV envelope protein structure to allow for a better immune response.
Similar to the CD4 protein that allows HIV to infect cells, the compound binds to the virus, making it detectable and therefore vulnerable to the immune system.
"Contrary to previous CD4 mimetic compounds, CJF-III-288 works at low doses on multiple primary HIV isolates," said Richard, the study's first author, a virologist and research associate in Finzi's lab at UdeM's affiliated hospital research centre, the CRCHUM.
"This new compound allows specific antibodies, known as anti-CoRBS, to trigger a cytotoxic reaction, called antibody-dependent cellular cytotoxicity (ADCC)," Richard added.
ADCC is one of the ways that the immune system gets rid of infected cells.
"Before this discovery, these antibodies were ineffective unless CD4-mimetic compounds and anti-cluster A antibodies were present," said Finzi, a researcher at CRCHUM and professor of virology at UdeM.
"This is the first time that we've demonstrated that anti-CoRBS antibodies can be effective by themselves, in combination with CD4-mimetic compounds," he said.
This new approach could be a significant step towards reducing viral reservoirs—dormant viral cells resistant to current treatments—that prevent people living with HIV to get rid of the virus.
Unparalleled viral flexibility
"To date, CJF-III-288 is the most potent CD4 mimetic compound that has been synthesized," said Finzi. "It creates an asymmetrical opening in the viral envelope, which gives it more flexibility. That's why it works so well."
"This structural flexibility allows anti-CoRBS antibodies to attack from different angles, facilitating the recognition of infected cells by natural killer cells, whose job it is to eliminate them."
"The presence of CJF-III-288 provides the flexibility that these antibodies, that were previously inactive, need in order to work effectively," added Richard.
This study is the result of close and fruitful collaboration with research teams in the United States specializing in disciplines ranging from animal modelling (Priti Kumar, Yale University) and chemistry (Amos B. Smith III, University of Pennsylvania), to cryo-electron microscopy (Marzena Pazgier, Uniformed Services University; Walther Mothes, Yale University) and real-time glycoprotein visualization (James Munro, University of Massachusetts).
Prevents viral rebound
In their research, the CRCHUM team began by demonstrating the efficacy of the new mimetic compound through tests on plasma samples from people living with HIV.
They also tested the molecule combined with anti-CoRBS antibodies on humanized mice, whose immune systems mimic humans'. When antiretroviral therapy on those mice was stopped, the treatment significantly delayed viral rebound.
Indeed, it took three times as long for the virus to reappear. In the test group of mice, HIV was detected again between 13 and 17 days after stopping treatment, compared to only five days in the control group.
"This delay in viral rebound indicates that the size of the viral reservoir was substantially decreased," says Finzi.
Though still in the preclinical phase, this scientific advance paves the way for new therapeutic strategies that would aim to eliminate infected cells, reducing the likelihood of requiring lifelong treatment.
Finzi and Richard now aim to combine CJF-III-288 mimetic compounds with cocktails of various antibodies and test its efficacy in non-human primates.
According to the World Health Organization, in 2024 nearly 41 million people were living with the virus that causes AIDS, with 1.3 million new HIV infections identified that year.
Author: Bruno Geoffroy
