Genetic Mutation for Severe COVID-19 Protects Against HIV Infection

A major genetic risk factor for COVID-19, inherited from Neandertals, significantly reduces the risk of contracting HIV.

COVID-19 disease severity has proven mysterious, with some people experiencing serious or fatal illness while others are virtually asymptomatic. In addition to advanced age and preexisting medical conditions, genetic heritage can affect COVID-19 severity.

One study found that a genetic mutation, passed down from our distant Neandertal ancestors, is a major risk factor for severe COVID-19. However, carriers of this risk variant may benefit from a 27% lower risk of HIV infection.

The study, published in PNAS, was solely authored by Hugo Zeberg, an assistant professor at the Karolinska Institutet. “This major genetic risk factor for COVID-19 is so common that I started wondering whether it might actually be good for something, such as providing protection against another infectious disease,” Zeberg said in a statement.

The genetic risk factor for COVID-19 severity is located in a multigene region on chromosome 3. Zeberg notes that there is no direct predictor for inheriting the risk haplotype, but it has carrier frequencies of 16% in Europe and 50% in South Asia.

In his study, Zeberg examined CCR1CCR2CCR3CCR5CCR9XCR1, and CXCR6, chemokine genes located within 0.55 megabases of the genetic variant. Zeberg used expression data from the blood of approximately 30000 donors and found that, with the exception of XCR1, all chemokine receptor genes were differentially expressed in donors who carried the risk variant.

The carriers had reduced expression for all genes but CCR9. The HIV-1 virus relies upon the CD4 to enter cells, though it also commonly uses the chemokine receptors CCR5, CXCR4, CCR3, and CXCR6.

Zeberg hypothesized that since individuals with the major genetic risk factor for COVID-19 have lower CCR5, CCR3, and CXCR6, HIV infection may be less prevalent in this group.

Zeberg conducted a meta-analysis of 3 available biobanks: the Michigan Genomics Initiative, the UK Biobank, and FinnGenn. Combined, the biobanks included 591 European persons with HIV infection. The meta-analysis yielded a risk ratio of 0.73 (95% CI: 0.59 to 0.90, P = 4.1e-3) in all 3 cohorts. Zeberg concluded that carriers of the chromosome 3 COVID-19 risk allele have a 27% reduced risk of contracting HIV.

The relevant DNA segment moderates the expression or several chemokine receptors, including the HIV coreceptor CCR5. The risk of HIV is downregulated in individuals who carry the COVID-19 risk haplotype.

Zeberg commented on the pros and cons of the genetic mutation: “The association described here highlights that gene flow from Neandertals was a double-edged sword. Whereas this genetic variant has had tragic consequences during the last 2 years in the COVID-19 pandemic, it appears to have offered considerable protection against HIV during the last 40 years. Its role in past and future pandemics remains to be seen.”