A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection

  • Nature. 2023 Aug;620(7972):128-136. doi: 10.1038/s41586-023-06331-x.
Danillo G Augusto  #  1  2  3 ,  Lawton D Murdolo  #  4 ,  Demetra S M Chatzileontiadou  #  4  5 ,  Joseph J Sabatino Jr  1 ,  Tasneem Yusufali  1 ,  Noah D Peyser  6 ,  Xochitl Butcher  6 ,  Kerry Kizer  1 ,  Karoline Guthrie  1 ,  Victoria W Murray  7 ,  Vivian Pae  7 ,  Sannidhi Sarvadhavabhatla  7 ,  Fiona Beltran  7 ,  Gurjot S Gill  7 ,  Kara L Lynch  8 ,  Cassandra Yun  8 ,  Colin T Maguire  9 ,  Michael J Peluso  7 ,  Rebecca Hoh  7 ,  Timothy J Henrich  10 ,  Steven G Deeks  7 ,  Michelle Davidson  11 ,  Scott Lu  12 ,  Sarah A Goldberg  12 ,  J Daniel Kelly  12  13 ,  Jeffrey N Martin  12 ,  Cynthia A Vierra-Green  14 ,  Stephen R Spellman  14 ,  David J Langton  15 ,  Michael J Dewar-Oldis  4 ,  Corey Smith  16 ,  Peter J Barnard  4 ,  Sulggi Lee  7 ,  Gregory M Marcus  6 ,  Jeffrey E Olgin  6 ,  Mark J Pletcher  12  17 ,  Martin Maiers  14 ,  Stephanie Gras  4  5 ,  Jill A Hollenbach  18  19
Affiliations
  • 1. Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA.
  • 2. Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC, USA.
  • 3. Programa de Pós-Graduação em Genética, Universidade Federal do Paraná, Curitiba, Brazil.
  • 4. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
  • 5. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
  • 6. Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA.
  • 7. Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
  • 8. Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
  • 9. Clinical and Translational Science Institute, University of Utah, Salt Lake City, UT, USA.
  • 10. Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
  • 11. Department of Medicine, University of California, San Francisco, CA, USA.
  • 12. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
  • 13. F.I. Proctor Foundation, University of California, San Francisco, CA, USA.
  • 14. CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN, USA.
  • 15. ExplantLab, Newcastle-upon-Tyne, UK.
  • 16. QIMR Berghofer Centre for Immunotherapy and Vaccine Development Brisbane, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • 17. Division of General Internal Medicine, University of California, San Francisco, CA, USA.
  • 18. Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA. [email protected].
  • 19. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 37468623 DOI: 10.1038/s41586-023-06331-x
Abstract

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic Infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic Infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic Infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

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