A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection, July 2023, Augusto, Peluso, Henrich et al

[EndME]

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

Abstract
Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1,2,3,4. 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.

https://www.nature.com/articles/s41586-023-06331-x

Once again the team surrounding Henrich, Peluso and Deeks at UCSF brings out a big paper albeit currently not directly relevant to Long-Covid.

 

[EndME]

A comment on this paper published in science: https://www.science.org/content/art...s-don-t-get-sick-gene-variant-may-explain-why.

 

[SNT Gatchaman]

(Pointed out by Deepti Gurdasani on social media - see below). You may recall the wave of paediatric fulminant hepatitis that occurred a year ago.

Although the data in our discovery cohort did not corroborate the association for HLA-DRB1*04:01 alone, we did find that this allele enhanced the effect of HLA-B*15:01 when the pair were in combination.

From the abstract for Adeno-associated virus 2 infection in children with non-A–E hepatitis (2023, Nature) —

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals.

Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4 + T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12 ).

She tweeted (Mastodon link to tweet) —

New study in @nature out yesterday, showing that HLA-B*15:01 and HLA-DRB1*04:01 are associated with strong T cell responses against SARS-CoV-2 & asymptomaticity- guess what other phenotype HLA-DRB1*04:01 has been associated with? Unknown fulminant hepatitis in children.

Remember all those studies in Nature, showing that unknown hepatitis in children was potentially down to a genetic association (and was attributed to Adv)- well the allele that 12/13 cases in one study carried is also related to strong T cell responses to SARS-CoV-2

Is this coincidence? It could be, but given the temporal association with the SARS-CoV-2 omicron wave, and that we know SARS-CoV-2 can be associated with post-inflammatory phenomenon like MIS-C, it's absolutely plausible that a stronger T cell response may have led to this.

Replying later —

Sure, it is saying that people with a particular set of genetic variants tend to have milder acute COVID when exposed to it, because they have a strong T cell response to COVID (potentially cross-reactive with other coronaviruses).

Coincidentally, the same set of genetic variants has also been associated with getting fulminant hepatitis in children - which has been attributed to adenovirus in some studies.

Many of us have said that the fulminant hepatitis of unknown cause seen in children was potentially a post-inflammatory complication of COVID-19 (similar to MIS-C). This provides some evidence towards this, as the same variant is associated with COVID-19 severity & hepatitis

So, it's very plausible that hepatitis arose in children who had these variants because they had a stronger T cell response to COVID- which may have meant 'milder' acute illness, but higher risk of post-acute infection inflammation (similar to MIS-C).

 

[SNT Gatchaman]

Back to this paper. This paragraph was interesting to me personally, as I'm HLA-B*07:02 and I think it's likely I had asymptomatic acute Covid.

This observation is in accordance with previous research in uninfected HLA-B*07:02 + individuals who are able to recognize the N(105–113) peptide derived from SARS-CoV-2 due to the presence of cross-reactive T cells recognizing the homologous N(105–113) peptide from OC43-CoV and HKU1-CoV. Notably, this T cell cross-reactivity has been associated with less severe COVID-19 disease.

That para references —

CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses (2021, Immunity)
An immunodominant NP105–113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease (2021, Nature Immunology)