Immunologists have long been trying to comprehend why similar viral infections give rise to diverse responses in different individuals. Until now, this was believed to be due to several complex mechanisms implemented by the immune system to tackle the infection. 

In a recent study, a group of scientists led by Narendra M Dixit from the Indian Institute of Science, Bengaluru, report a contrasting theory that outcomes of viral infections are dependent primarily on the interplay of only two factors: infection-triggering agents called antigens and specialized immune cells called CD8 T cells.

Viral infections baffle us: some are rapidly cleared in a few days by the immune system (such as the common cold), while others such as HIV give rise to a persistently infected state, while yet others such as Ebola or swine flu cause rapid deterioration, even leading to death. Sometimes, the same virus causes different outcomes in different individuals. For example, Hepatitis C infections are seen to spontaneously clear in 30% of the people infected, whereas it can turn chronic in others. 

When viruses attack healthy cells, they use them as replicating factories to proliferate. Viruses carry structures called antigens which can trigger the immune system. In response to the invasion, the immune system immediately summons a host of immune factors and killer cells. Among them, specialised cells called CD8 T cells are equipped with receptors that can identify the antigen patterns on the infected cells. CD8 T cells immediately attack the infected cells and destroy them to arrest the progression of the infection.

In turn, the virus generates chemicals to ward off the CD8 T cells. If the virus is aggressive or present in large numbers, it can overwhelm the killer cells and induce cell exhaustion, wherein the cells lose their vigour and multiplying capacity. 

“In the course of this battle, the major factor that determines the outcome of the infection is the balance between CD8 T cell activity and exhaustion,” says Dixit. If the CD8 T cells overpower the virus, the infection is cleared. However, if they are exhausted, the infection persists and can turn into a chronic condition.

The researchers observed that all other cellular factors released during the initial immune response act as mediators or modulators for this primary interaction between the antigens and CD8 T cells. The study also found that there exists a threshold for cell exhaustion, based on the balance between antigen load and CD 8 T cell numbers.

Dixit’s team explored the possibility of arriving at a unified explanation based on their observations. They devised a simple mathematical model to encode the dynamics of the events and variables associated with viral infections. 

Their model describes disease progression based on the balance of antigen-CD8 T cell interaction, factoring in the strength and severity of the infection at the start. Also, the model gives an estimate of the threshold level of CD8 T cells required to overcome the infection.

Soumen Basak, Staff Scientist at the National Institute of Immunology (NII), New Delhi, who was not connected with the study, says, ​“Such experimentally verified computational models offer powerful tools for advancing immunology research. They enable a quantitative mechanistic analysis of intricate immune processes, and can direct novel discoveries because of their predictive capabilities.”

Dixit claims that the new theory proposes ways to alter the outcomes of viral infections. Understanding the interactions that determine infection outcome would help researchers devise interventions to suitably modulate these key interactions and cure chronic infections. Also, biochemical modifications may raise the CD8 T cell exhaustion thresholds, paving the way for new treatments. 

“The research provides not only testimony to these claims but also bears promise for improved anti-viral therapeutic strategies. Tweaking of the core circuit might allow the elimination of persistent viral infection without provoking immunopathology,” says Basak.

In the meantime, the work shows promise for both basic and translational research on anti-viral immunity and anti-viral therapy.

Commenting on this, Satyajit Rath, Adjunct Professor at the Indian Institute of Science Education and Research (IISER), Pune, who was also not connected with the study says, ​“The model can drive more refined empirical work so that it can make quantitative and testable predictions, thereby allowing conceptual and translational advances in the future.” 

Did you enjoy this article? Please let us know in the comments below.