Vaccine and Infectious Disease Division

How our immune system recognizes rapidly evolving viruses

Human leukocyte antigens, or HLAs, are part of a key step in the immune system’s recognition of foreign invaders.  They reside on the outer surface of many of our cells and present bits of foreign proteins to train T cells to recognize that specific pathogen.  The genes coding for HLAs are thought to be among the most rapidly evolving in the human genome, as they must adapt quickly to viruses that are also rapidly mutating to escape the human immune system.  But viruses have a major advantage in that their life cycles are much shorter than ours, so are able to mutate more quickly.

To determine how HLAs manage to keep up in this evolutionary arms race, VIDD staff scientist Dr. Tomer Hertz and colleagues devised computational methods to study how HLA molecules recognize foreign invaders.  The researchers compared predicted binding strengths between each possible pair of 95 HLA alleles and nine-amino-acid-long peptides from nearly 5000 human proteins, and the proteomes of 52 common human viruses.  They found that in most cases, HLA molecules tend to target evolutionarily conserved regions of proteins.  They also found that one class of HLA molecules, HLA-A, preferentially targets DNA viruses, while the HLA-B class tends to target RNA viruses.

“This also allows a single HLA to have a kind of ‘silver bullet’ effect,” Hertz said.  “If an HLA binds a conserved and important sequence on a viral protein, which the virus simply cannot mutate, that means that a single HLA can offer protection from that pathogen.”

Hertz T, Nolan D, James I, John M, Gaudieri S, Phillips E, Huang JC, Riadi G, Mallal S, Jojic N.  Mapping the Landscape of Host-Pathogen Coevolution: HLA Class I Binding and Its Relationship with Evolutionary Conservation in Human and Viral Proteins.  J Virol. 2011 Feb;85(3):1310-21.