A study recently published in the journal Top Proceedings of the National Academy of Sciences of the United States of America (PNAS) shows how a specific gene stream from Neanderthals can act as a double-edged sword by increasing the risk of developing severe coronavirus disease 2019 (COVID-19), while reducing the risk of infection with the human immunodeficiency virus (HIV).
Examination: The major genetic risk factor for severe COVID-19 is associated with protection against HIV. Image credit: IR Stone / Shutterstock
During the ongoing COVID-19 pandemic, many basic research studies have been pursued to uncover prominent risk factors for serious forms of the disease. From the genetic perspective, the severity of COVID-19 can be linked to chromosome 3 and specifically to a genomic region encoding chemokine receptors that act as mediators of different cellular responses.
Previous studies have shown that these specific genetic risk factors have been introduced into the modern human population from an extinct species of archaic humans known as Neanderthals about 50 to 70 thousand years ago.
Although there is no direct evidence of positive selection on this group of genes inherited together from one parent (also known as haplotype), so we its frequency has increased since the last ice age maximum.
Today, this gene set is unusually widespread and common, with carrier frequencies ranging from 16% to 50% on the European continent and South Asia, respectively. It is therefore very interesting to consider whether it may have certain beneficial properties.
“This large genetic risk factor for COVID-19 is so common that I began to wonder if it could actually be good for something, such as providing protection against another infectious disease,” says the author of the newspaper Hugo Zeberg of the Max Planck Institute for Evolutionary anthropology in Leipzig (Germany) and Karolinska Institutet in Stockholm (Sweden).
A story about chromosome 3
Many chemokine receptor genes found on chromosome 3 – more specifically CCR1, CCR2, CCR3, CCR5, CCR9, CXCR6 and XCR1 – are all located within 0.55 megabases of the genetic variant, which is likely to increase the risk of developing severe COVID-19.
One of these receptors is involved in the HIV infection process, as it allows the virus to enter white blood cells in humans, as well as to spread from cell to cell. This receptor is known as CCR5 and it basically acts as a co-receptor along with the main receptor CD4. And since the individuals carrying the greatest genetic risk factor for COVID-19 have lower CCR5 levels (along with CCR3 and CXCR6), Drs. Zeberg that they could also have lower incidence of HIV infection.
Reduces the risk of HIV infection
Using whole blood expression data from approximately 30,000 individuals, Dr. Zeberg initially states that all of the aforementioned chemokine receptor genes (with the exception of XCR1) are differentially expressed in those carrying the risk variant, with reduced expression for all genes except CCR9.
In this paper, he also conducted a meta-analysis of three of the largest biobanks currently available: Michigan Genomics Initiative, UK Biobank and FinnGen. These cohorts contain 591 European individuals with HIV infection as well as 667,215 controls.
In a nutshell, his main finding was that the carriers of chromosome 3 COVID-19 risk allele have a 27% reduction in the risk of HIV infection – without any detectable heterogeneity across the analyzed cohorts.
A genetic example of a double-edged sword
Nevertheless, since the rise in HIV took place during the 20sth century, protection against this specific virus could not justify the spread of genetic risk variants of COVID-19 among humans as early as ten thousand years ago.
“Now we know that this risk variant for COVID-19 provides protection against HIV. But it was probably protection against another disease that increased its frequency after the last ice age,” Dr. Zeberg emphasizes.
Smallpox may be a likely candidate since a causative variola virus emerged more than ten thousand years ago. Yersinia pestisa bacterial pathogen that causes plague can also be considered, although this species appeared later (i.e., about seven thousand years ago).
In any case, this genetic variant is a double-edged sword: it came with tragic consequences over the last two years, while the COVID-19 pandemic raged, but on the other hand, it offered significant protection against HIV for the last forty years. Its role in past and future pandemics needs to be elucidated.