A new study shows how key features on the surface of HIV-infected cells such as certain sugar molecules help the disease evade detection by the immune system, and how they can be disabled. The findings, published in PLOS Pathogens, represent a first step to eradicating this persistent virus in patients.
“We identified a glyco-immune checkpoint interaction as a novel mechanism that allows HIV-infected cells to evade immune surveillance,” said Mohamed Abdel-Mohsen, PhD, assistant professor in the Vaccine & Immunotherapy Center at The Wistar Institute and coauthor on the paper. “And we developed a novel approach that selectively targets these interactions on the surface of these infected cells.”
Existing treatments can reduce HIV to undetectable levels, but eradication remains elusive, with the disease typically returning quickly when treatment stops. And even when controlled, HIV increases risk for other health problems, including neurological disorders, cardiovascular disease, and cancer.
For the new study, researchers looked at a type of sugar molecule called sialic acid on the surface of HIV-infected cells. These sugars bind with receptors called siglecs on the surface of disease-fighting ‘natural killer’ immune cells. When activated, these receptors act as inhibitors, restraining the killer cells and causing them to stop killing. “We thought, ‘is it possible that these HIV-infected cells are using this interaction – covering themselves with these sugars to evade the natural killer immune surveillance?’” said Prof Abdel-Mohsen.
The researchers found that these infected cells can actually exploit this inhibitory connection to evade immune surveillance. They then investigated whether they could manipulate this connection to make the killer cells more effective at killing HIV-infected cells. Disabling the inhibitors from the killer cells was found to cause the immune cells to attack indiscriminately. The researchers turned to the HIV cells, using the enzyme sialidase to remove the sialic acid sugars that were activating the immune inhibitors but this affected all cells, again causing the killer cells to attack indiscriminately. Finally, they developed a sialidase conjugate linked to HIV antibodies, which only targeted sialic acid on HIV cells. With the sialic acid removed from these cells, the killer immune cells attacked and killed the HIV-infected cells, leaving healthy cells alone.
“The killer cells become a super killer for the HIV-infected cells and they now attack them in a selective manner,” said Prof Abdel-Mohsen. “The discovery could be a missing link in the “shock and kill” approach to HIV treatment that has been a focus of research for the past several years,” he added. This two-step process involves first “shocking” the HIV out of latency so it can be detected, and then stimulating the immune system to “kill” the virus once and for all. However, while effective methods have been discovered to reverse latency, scientists haven’t yet found a way to make HIV-infected cells more killable once reactivated. “We may have the shock, but we don’t yet have the kill,” Prof Abdel-Mohsen said. “Our method actually increases the susceptibility of HIV-infected cells to killing, which is one of the top unmet needs in the HIV field.”
First author Samson Adeniji, Ph.D., a postdoctoral fellow at Wistar, noted that the team’s approach could be tested in combination with broadly neutralizing antibody therapies currently being studied in clinical trials. “By combining approaches, we could turn these immune cells from a cop into a kind of Robocop,” he said.
The researchers also noted that, besides HIV, the approach could be applied in infectious diseases that may evade the immune system, including hepatitis and COVID. In vivo tests with animals are the next step. They’re also investigating other sugar molecules on HIV that may play a similar role as sialic acid. “HIV-infected cells are likely evading immune surveillance through many potential glyco-immune checkpoints,” Abdel-Mohsen said. “We are investigating other mechanisms and how to break them.”
Source: Wistar Institute
