Neanderthal Gene Increases Risk of Severe COVID-19 but May Offer Protection Against HIV
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A new study has identified an association between a genetic variant that increases the risk of developing severe COVID-19 and protection against HIV infection. The research is published in the Proceedings of the National Academy of Sciences (PNAS) journal.
Clinical variability in COVID-19 patients
Two years after the global COVID-19 pandemic was declared, our understanding of why some patients become more ill than others – known as clinical variability – has grown. Several research studies have been published that identify risk factors underpinning disease susceptibility and severity, including age, underlying health issues and our genetic constitution.
In 2020, a research duo from the Karolinska Institute and the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) published a paper demonstrating that a specific gene cluster – located on chromosome three – increases susceptibility for severe COVID-19 and was inherited from the Neanderthals.
“It turns out that this gene variant was inherited by modern humans from the Neandertals when they interbred some 60,000 years ago,” Dr. Hugo Zeberg, assistant professor at the Karolinska Institute and co-author of the paper said. “Today, the people who inherit this gene variant are three times more likely to need artificial ventilation if they are infected by the novel coronavirus SARS-CoV-2.”
Zeberg, who studies gene flow from Neanderthals and Denisovans into modern humans, worked alongside Professor Svante Pääbo, director of the MPI-EVA to on this research and a subsequent publication that examined the frequency of the gene cluster in modern humans. “Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 years ago and again during the past 1,000 years,” the authors wrote.
The variant is “unusually common” in modern populations, which led Zeberg to hypothesize that it might serve other, more favorable impacts on humans, by providing – for example – protection against other diseases, like the human immunodeficiency virus (HIV).
Chemokine receptors, COVID-19 and HIV
Zeberg conducted a meta-analysis of three large biobanks, the UK Biobank, the Michigan Genome Initiative and Finngen. A total of 591 European participants with HIV and 667,215 controls were included in the analysis. “I compared how common this variant [the COVID-19 risk variant] is among those infected and those not infected with HIV,” Zeberg says in an interview with Technology Networks.
Why did Zeberg choose to look at HIV, specifically? The gene cluster located on chromosome three lies within a genomic region that encodes various chemokine receptors. Chemokines are signaling molecules that play key roles in the human immune system and inflammatory responses. Zeberg found that individuals carrying the COVID-19 risk variant have reduced expression of chemokine receptor genes CCR1, CCR2, CCR3, CCR5.
The CCR5 gene encodes the C-C chemokine receptor type 5 (CCR5), a G-protein coupled receptor that is expressed primarily on the surface of T cells, dendritic cells, macrophages, microglia and some cancer cells. The human immunodeficiency virus 1 (HIV-1) enters immunological cells via a mechanism that co-utilizes CCR4 and CCR5. If the CCR5 gene is downregulated in individuals that carry the COVID-19 risk variant, Zeberg wondered if it would confer some level of protection against HIV.
From the biobank data, Zeberg discovered an association: individuals carrying the COVID-19 risk allele on chromosome three had a 27% reduction in the risk of HIV infection.
HIV arose in the 20th century and thus the study data does not provide an explanation as to why the variant was “unusually common” in human beings up to ~10,000 years ago. “At this point I could only speculate about what disease drove the increase in frequency 10, 000 years ago. Smallpox is my best bet, at the moment,” Zeberg says.
A double-edged sword
A limitation of the work, Zeberg highlights, is that it is an association study: “This research needs to be followed up by laboratory studies,” he explains, adding that with further understanding, it may be possible to stratify people – or populations – in terms of their risk for HIV infection.
Zeberg and colleagues are currently conducting functional experiments to understand why the variant increases the risk of severe disease in COVID-19 patients.
“The association described here highlights that gene flow from Neanderthals was a double-edged sword. Whereas this genetic variant has had tragic consequences during the last two years in the COVID-19 pandemic, it appears to have offered considerable protection against HIV during the last 40 years,” Zeberg writes.
Dr. Hugo Zeberg was speaking to Molly Campbell, Senior Science Writer for Technology Networks.
Reference: Zeberg H. The major genetic risk factor for severe COVID-19 is associated with protection against HIV. PNAS. 2022. doi: 10.1073/pnas.2116435119