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

Danillo G. Augusto, Lawton D. Murdolo, Demetra S. M. Chatzileontiadou, Joseph J. Sabatino, Tasneem Yusufali, Noah D. Peyser, Xochitl Butcher, Kerry Kizer, Karoline Guthrie, Victoria W. Murray, Vivian Pae, Sannidhi Sarvadhavabhatla, Fiona Beltran, Gurjot S. Gill, Kara L. Lynch, Cassandra Yun, Colin T. Maguire, Michael J. Peluso, Rebecca Hoh, Timothy J. Henrich, Steven G. Deeks, Michelle Davidson, Scott Lu, Sarah A. Goldberg, J. Daniel Kelly, Jeffrey N. Martin, Cynthia A. Vierra-Green, Stephen R. Spellman, David J. Langton, Michael J. Dewar-Oldis, Corey Smith, Peter J. Barnard, Sulggi Lee, Gregory M. Marcus, Jeffrey E. Olgin, Mark J. Pletcher, Martin Maiers, Stephanie Gras and Jill A. Hollenbach ()
Additional contact information
Danillo G. Augusto: University of California
Lawton D. Murdolo: La Trobe University
Demetra S. M. Chatzileontiadou: La Trobe University
Joseph J. Sabatino: University of California
Tasneem Yusufali: University of California
Noah D. Peyser: University of California
Xochitl Butcher: University of California
Kerry Kizer: University of California
Karoline Guthrie: University of California
Victoria W. Murray: University of California
Vivian Pae: University of California
Sannidhi Sarvadhavabhatla: University of California
Fiona Beltran: University of California
Gurjot S. Gill: University of California
Kara L. Lynch: University of California
Cassandra Yun: University of California
Colin T. Maguire: University of Utah
Michael J. Peluso: University of California
Rebecca Hoh: University of California
Timothy J. Henrich: University of California
Steven G. Deeks: University of California
Michelle Davidson: University of California
Scott Lu: University of California
Sarah A. Goldberg: University of California
J. Daniel Kelly: University of California
Jeffrey N. Martin: University of California
Cynthia A. Vierra-Green: CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match
Stephen R. Spellman: CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match
David J. Langton: ExplantLab
Michael J. Dewar-Oldis: La Trobe University
Corey Smith: QIMR Berghofer Medical Research Institute
Peter J. Barnard: La Trobe University
Sulggi Lee: University of California
Gregory M. Marcus: University of California
Jeffrey E. Olgin: University of California
Mark J. Pletcher: University of California
Martin Maiers: CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match
Stephanie Gras: La Trobe University
Jill A. Hollenbach: University of California

Nature, 2023, vol. 620, issue 7972, 128-136

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06331-x

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