Oral Presentation 14th Lorne Infection and Immunity 2024

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection (#9)

Dimitra SM Chatzileontiadou 1 2 , Lawton D Murdolo 1 , Danillo G Augusto 3 4 5 , Joseph J Sabatino Jr 3 , Stephanie Gras 1 2 , Jill A. Hollenbach 3 6
  1. La Trobe University, Bundoora, VIC, Australia
  2. Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, VIC, Australia
  3. Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
  4. Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC, US
  5. Programa de Pós-Graduação em Genética, Universidade Federal do Paraná, Curitiba, Brazil
  6. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

Throughout the COVID-19 pandemic, research has centred on understanding why some people infected with the SARS-CoV-2 virus experience severe disease. However, 10-30% of individuals with the virus do not show any symptoms. Investigating asymptomatic infection could shed light on features of the immune system that help to eliminate SARS-CoV-2. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we investigated the genetics of almost 30,000 registered bone marrow donors who participated in a voluntary program to track COVID-19 infection and symptoms1. Our analysis revealed 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 Spike-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 (NQKLIANAF). The crystal structure of HLA-B*15:01–peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF 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 immunity1. Our findings have major implications for public health because such knowledge could inform the design and development of vaccines and therapies for COVID-19. More broadly, identifying genetic factors that control the course of the disease could begin to explain the wide variation in how people respond to SARS-CoV-2 and other viral infections.


  1. 1 Augusto DG, Murdolo LD, Chatzileontiadou DSM, et al. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection, Nature, 2023, 620(7972):128-136.