Investigating HIV’s Hidden Immune Evasion Strategy 

A Northwestern Medicine study published in Nature Communications has revealed how HIV can protect infected cells by altering the sugars on their surface, hindering the host immune system and avoiding detection. 

The study also lays the foundations for a new therapeutic approach that could strengthen the fight against the virus, said study senior author Mohamed Abdel-Mohsen, PhD, the Margaret Gray Morton Professor of Medicine in the Division of Infectious Diseases. 

Antiretroviral therapy, or ART, is the current standard therapy for HIV. Although ART suppresses viral replication, it does not cure HIV, and the virus can rebound when treatment is discontinued. 

“This rebound is because there are many HIV infected cells that can still hide in the blood and in tissues. They escape immune surveillance, but we didn’t know exactly how they do this,” Abdel-Mohsen said. 

In the study, Adbel-Mohsen and his collaborators used advanced glycomic analysis and gene-editing techniques to show that HIV infection reprograms the glycosylation machinery of infected cells, surface sialic acid-containing glycans (sialoglycans) on infected cells and effectively “cloaking” them. These sialoglycans engage inhibitory Siglec receptors, a family of glycan-binding receptors on immune cells that function as “glyco-immune checkpoints.” This interaction suppresses immune cells from fighting the virus, allowing HIV to escape immune surveillance.  

To counter this sugar-based immune evasion phenomenon, the team developed an experimental therapy combining an HIV-specific antibody with sialidase, an enzyme that strips away sialic acids. The antibody is intended to guide the enzyme to HIV-infected cells, strip away excess sialoglycans that engage inhibitory Siglec receptors, and thereby increase susceptibility to immune-mediated killing while minimizing effects on uninfected cells. In cultured cells and in laboratory mice, this approach significantly boosted immune cell killing of HIV-infected cells, reduced viral load and lowered inflammation, according to the study. 

“Basically, HIV uses a wolf-in-sheep’s-clothing trick to dampen the immune response,” Abdel-Mohsen said. “We strip away that disguise and allow the immune cells to see it for what it is.” 

The findings not only uncover a previously unrecognized immune evasion mechanism but also point to a promising new strategy for HIV treatment by targeting sugar-cell interactions to enhance immune responses. 

Additionally, the findings highlight a broader immunology principle: inhibitory sialoglycan–Siglec interactions can dampen immune effector functions, a framework that may also help interpret immune evasion in other contexts, including cancer. 

“Here, we identified a novel glycan-based mechanism by which HIV infected cells trick our immune system by engaging inhibitory glyco-immune checkpoints, a theme that has also been reported in cancer,” Abdel-Mohsen said. “I find it fascinating that very different ‘sick’ cells, cancer and virus-infected, converge on the same sugar-based immune evasion. It highlights how important glycans are for controlling immune responses and why they are actionable targets.” 

Now, Abdel-Mohsen and his collaborators will test their therapeutic approach in mice on ART, more closely mimicking the molecular environment of a human HIV patient.  

“Our goal is to add this approach to the toolbox to reach what is called a functional cure for HIV — not necessarily eliminate every single infected cell, but enough that a person can live without antiretroviral therapy and be in remission,” said Abdel-Mohsen, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  

Additional Feinberg co-authors included Shalini Singh, PhD, S. M. Shamsul Islam, PhD, and Pratima Saini, PhD, members of the Abdel-Mohsen laboratory; Leila B. Giron, PhD, research assistant professor of Medicine in the Division of Infectious Diseases; Judd Hultquist, PhD, the Dr. Robert L. Murphy Professor of Emerging Infectious Diseases and Lacy M. Simons, PhD, a scientist in the Hultquist laboratory.

The study was supported by National Institutes of Health grants R01AI165079, R01AG092241, R01AA029859, R01DK123733, and R01NS117458.