HIV ravages the immune system in people who acquire it, but not everyone is affected equally. In some of these individuals, the effects of the virus don’t manifest as swiftly as in others. 

Scientists have long recognized that people’s genes and the proteins they encode play a role in why this is. Now, a team in Frederick National Laboratory’s Basic Science Program and their collaborators have established a direct way to measure one such factor. Their findings appear in Science

The team dubbed the measurement “functional divergence” and used it to demonstrate that variation in human leukocyte antigen (HLA) proteins in people living with HIV affects the severity of their condition. 

Through their calculations, they showed that having a collection of HLA proteins with greater functional divergence—the ability to bind a breadth of viral peptides—correlated with slower progression toward severe immunodeficiency in people living with HIV. It confirms what scientists long knew but couldn’t precisely measure: that diversity in HLA proteins can have immunological benefits against the virus. 

While the technique can illuminate the immune system’s responses to HIV, the team expects it has applications to other infectious diseases, as well as various cancers. HLA proteins are involved in the immune response to all of these conditions. 

Better than a blueprint 

HLA proteins are a key component of the immune system, with different kinds dotting the surface of human cells. When a cell becomes infected with a virus, such as HIV, it transports viral peptides—small fragments of the virus—to the HLA proteins, which hold them in place like a flag or signal flare on the cell’s surface. T cells, a type of white blood cell, detect these peptides and take the cue to attack: the cell is infected and must be destroyed to help stem the virus’ spread. 

The catch is that each one of the many types of HLA proteins is suited to grasp only representatives from a specific set of peptides, and different people have different combinations of HLA proteins. Everyone receives one set of HLA genes from their mother and one from their father. Depending on their parents’ DNA, the genes and the HLA proteins they encode may be similar or vastly different. 

“There’s a need to accommodate numerous distinct sets of peptides, and it’s done by having these differences between multiple [HLA] copies that segregate in the population,” said Colm O’hUigin, Ph.D., co-lead author on the study alongside Mathias Viard, Ph.D. Both O’hUigin and Viard are part of the Basic Science Program. 

Functional divergence measures the different repertoires of viral peptides a person’s HLA proteins can grasp. It improves on previous methods, which tried to gauge what HLA proteins were capable of grasping by examining the differences in the HLA genes. Measuring functional divergence is like examining a piece of machinery directly rather than trying to ascertain its capabilities by studying the blueprint. 

“We are delighted to have developed a metric that provides greater sensitivity and discrimination than the simple, less robust genetic heterozygosity concept,” said Mary Carrington, Ph.D., Basic Science Program director and the senior author on the study. 

The team examined blood samples from multiple cohorts of people living with HIV, including cell bank samples from untreated persons who provided blood in the years before antiretroviral therapy was available. The results followed the same trend in every group. 

The study builds on past contributions from decades-long research in the field. Carrington and colleagues showed in 1999 that people with HIV who had largely similar repertoires of HLA proteins fared poorly. 

A chance for broader use 

Given HLA’s involvement in defending against other health conditions, the scientific community may be able to study functional divergence in other diseases. However, the team cautions that translating it won’t be clear-cut due to each disease’s uniqueness. Differences between diseases could affect scientists’ ability to determine the role of functional divergence in other scenarios. 

Further studies will therefore be required before the measurement can be applied in certain situations beyond HIV. The team say their study has moved the analysis closer to where the biological phenomena are happening but that it’s reasonable to expect additional research to tweak it for other diseases. 

Still, they expect it’ll work in many contexts, even if it requires some adaptation. The underlying principles are similar, they say. 


In addition to Frederick National Laboratory, researchers representing the Ragon Institute of Massachusetts General Hospital; the Feinberg School of Medicine; the San Francisco Department of Public Health; the University of California, San Francisco; the Bloomberg School of Public Health at Johns Hopkins University; the National Cancer Institute; the U.S. Military HIV Research Program; the Vanderbilt University School of Medicine; and the Howard Hughes Medical Institute contributed to the study. 

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