In the arms race between virus and immune system for survival, both have accepted trade-offs to get a leg up over the other.
New research on tuberculosis (TB) and HIV has shed light on the evolutionary compromises both pathogens and host immune systems make in their efforts to outwit one another.
A receptor meant to protect — until it doesn’t
Scientists from the University of Exeter have revealed that TB harnesses a part of the immune system that is meant to protect against infection.
This explains why humans and animals are so susceptible to contracting TB.
TB is caused by the bacterium Mycobacterium tuberculosis (MTB). Infection occurs when the bacteria are inhaled and taken up by specialist immune cells, such as macrophages, which recognise MTB and trigger a range of cellular and immune responses.
These responses are mediated by receptors — molecules on the surface of immune cells that can recognise microbes.
One such receptor is Dectin-1, which is best known for its role in anti-fungal immunity.
MTB has evolved a range of strategies to overcome the immune system's defences, including targeting Dectin-1 to survive within the cells of its host.
In work supported by Wellcome and the Medical Research Council, the team showed that instead of protecting against infection, as occurs during fungal infection, MTB utilises the responses triggered by Dectin-1 to drive its own survival.
When this Dectin-1 pathway was absent, both human and mouse cells could control MTB infection. Indeed, mice lacking Dectin-1 were much more resistant to MTB infection.
The team, made up of Osaka University, the University of Cape Town and the Francis Crick Institute and others, also discovered that the bacteria produce a unique molecule called alpha-glucan to target Dectin-1 to induce these determinantal immune cell responses.
Dr Max Gutierrez, of the Francis Crick Institute, said: "TB is a major killer worldwide, yet we still know very little about how it is so effective at causing infections, in both humans and in animals."
"Our discovery of a new mechanism by which Mycobacterium tuberculosis can subvert host immunity is a key step in understanding the basis of susceptibility to TB."
The research findings were published in Science Immunology, giving new insight into how TB takes hold to cause disease.
The price of protection: HIV’s resistance trade-off
On the other hand, analysis by Gilead has identified the trade-off that HIV has made in its evolution to resist the breakthrough antiviral lenacapavir
Researchers have shown that HIV can develop resistance to lenacapavir by altering the structure of its capsid protein, reducing the drug’s ability to bind.
However, these resistance mutations come at a significant cost to viral fitness, severely impairing replication.
The findings, published in Science Translational Medicine, suggest that lenacapavir-resistant strains are unlikely to spread widely.
This reinforces the importance of resistance surveillance and the use of fully active companion antivirals to limit the emergence of resistance.
Lenacapavir, approved in 2022 as Sunlenca for multidrug-resistant HIV, is the first approved therapy to target the viral capsid, which protects the virus’s genetic material.
Its novel mechanism prompted researchers to investigate whether HIV could evolve to evade capsid inhibition.
Analysing samples from Gilead’s Phase II CALIBRATE and Phase III CAPELLA trials, researchers identified three key capsid mutations that reduced lenacapavir binding.
The most common involved a methionine-to-isoleucine substitution, which conferred high-level resistance but reduced viral replication capacity to below 20% of normal levels.
In several patients, viral suppression was maintained due to this trade-off between resistance and replication. Importantly, resistance to lenacapavir did not confer cross-resistance to other antiviral classes.
The study adds to growing evidence that resistance to lenacapavir remains rare and supports combination therapy, improved resistance monitoring and the development of next-generation capsid inhibitors.