A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection
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Abstract
Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic 1–4 . 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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SciScore for 10.1101/2021.05.13.21257065: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Data collection: This study was conducted in accordance with the ethical standards of the UCSF Human Research Protection Program Institutional Review under approval #20-30850 and informed consent was obtained from all individual participants involved in the study. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data collection: This study was conducted in accordance with the ethical standards of the UCSF Human Research Protection Program Institutional Review under approval #20-30850 and informed consent was obtained from all individual participants involved … SciScore for 10.1101/2021.05.13.21257065: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Data collection: This study was conducted in accordance with the ethical standards of the UCSF Human Research Protection Program Institutional Review under approval #20-30850 and informed consent was obtained from all individual participants involved in the study. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data collection: This study was conducted in accordance with the ethical standards of the UCSF Human Research Protection Program Institutional Review under approval #20-30850 and informed consent was obtained from all individual participants involved in the study. UCSF Human Research Protection Programsuggested: NoneSubjects were volunteer bone marrow donors with valid email addresses on file with the National Marrow Donor Program (NMDP) who were invited to participate in the study through an email outreach campaign that began in July 2020. National Marrow Donor Programsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:A key limitation of this study is that all testing results and symptoms are self-reported. We recognize that this may result in some margin of error in our results. However, we have previously validated this approach by verifying test results in a subset of the participants.48 Additionally, we note that we find a remarkably consistent genetic association across the study, pointing to a true biological feature. Likewise, some key differences were observed between the discovery and replication phase of our study. For example, differences in SARS-CoV-2 positivity results between the first (5%) and second (17%) stages may be explained by the overall trajectory of the pandemic in the United States. The discovery cohort primarily comprises individuals enrolled relatively early in the pandemic, while the replication cohort enrolled at the height of the winter surge. Likewise, the lower rate of asymptomatic infection in the replication cohort (5.8% vs 14.1% in discovery) may be attributed to many factors related to change over time in the pandemic; such as, the prevalence of more virulent viral variants or shifts in public utilization of testing. We also observed significantly older age in asymptomatic individuals compared to those who developed symptomatic infection. This difference may be at least in part explained by subjects’ self-reported reasons for seeking testing for the virus. Perhaps unsurprisingly, the most common reason patients reporting symptomatic infection sought test...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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