Adaptive immune responses to SARS-CoV-2 differ with HLA genetic variation

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Researchers at the University of Geneva (Switzerland) have classified variations of the human leukocyte antigen (HLA) protein in order to identify those that bind the most strongly to the peptides of the novel coronavirus, SARS-CoV-2. The study, published in HLA: Immune Response Genetics, provides insight into the reasons for differences in COVID-19 susceptibility between populations.  

HLA molecules present on the cell’s surface bind to peptides of an infecting virus, triggering an immune response.

Using bioinformatic analysis, the team identified HLA variants and their frequencies in different human populations. Alicia Sanchez-Mazas (Unversity of Geneva), one of the study’s authors, explained: “from the 450 or so most common HLA molecules in hundreds of populations worldwide, we tried to identify the ones that are most strongly bound to the peptides of the new coronavirus.”

The HLA molecules were classified based on how easily they were able to bind to coronavirus peptides, which goes some way towards explaining the differences observed in resistance or susceptibility to the virus between individuals. José Manuel Nunes (University of Geneva), another co-author of the study, gave an example: “we were surprised to find that Indigenous populations in America had both the highest frequencies of HLA variants that bind the most strongly to the peptides and the lowest frequencies of those that bind the least strongly.”

While informative, the results are only part of a much larger picture when it comes to variation in the overall immune response: “HLA molecules contribute to the immune response but they are far from being the only element that can be used to predict effective or ineffective resistance to a virus,” continued Nunes. “This is also verified on the ground since America’s Indigenous populations are apparently no less affected than others by COVID-19.”

Some HLA-peptide interactions showed strong binding affinities across peptides from all seven viruses studied. Termed “generalist” HLA molecules, these variants were effective in immune responses to a number of viruses. The researchers observed differing frequencies of generalist HLA variants between populations, but not specific differences in affinity for peptides of the new coronavirus.

The next steps for the researchers will be to find the coronavirus peptides that bind most strongly to HLA molecules. These will be the most likely to trigger an immune response across variants and therefore promising candidates for developing a vaccine.

Sources: Barquera R, Collen E, Di D et al., Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide. HLA: Immune Response Genetics (2020) doi:10.1111/tan.13956; www.unige.ch/communication/communiques/en/2020/were-not-all-equal-in-the-face-of-the-coronavirus/

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