People with a protective mutation against HIV have a reduced life expectancy

At the end of last year, a Chinese researcher shocked the scientific community by announcing that the first gene-modified humans were already born. He went beyond a nascent consensus that the technology was not ready for use and, once it was, should be reserved for diseases that would otherwise not have been treated. Instead of meeting these limits, he did much of his work without any clear institutional oversight.

Instead of tackling an incurable genetic disorder, He Jiankui focused on something for which we have both preventive measures and treatments: HIV infection. He did this by using the CRISPR gene editing to damage a gene that encodes a protein that HIV uses to enter human cells; Previous studies have shown that mutations of this gene protect against HIV infection. But the same mutation was already known to make humans more susceptible to other diseases, asking whether gene editing was putting its recipients at risk.

This question has now been answered with a categorical "yes". The researchers found that adults carrying mutations in the gene saw their overall mortality increase by 20% compared to their peers.

Big Data

The gene in question is called CCR5, and it encodes a receptor for immune signaling proteins. To fulfill this function, he must sit on the surface of immune cells, where HIV can catch him and use it to take a ride inside the cell, where he can continue a infection. The research found that some people whose HIV infection progressed slowly often exhibited mutations CCR5, often a specific mutation called Δ32, which causes severe damage to the protein.

CCR5-32 mutations occur at a low level in the general population, and it is protective at a time when it is present in one or both gene copies. Using knowledge of its role in HIV infections, researchers used CCR5-Δ32 donors to provide new blood stem cells to two patients with HIV-positive leukemia, a transplant that has managed to eliminate the virus from these people.

The He Jiankui gene edition was intended to provide protection against HIV to children of an HIV-positive parent. This, to a certain extent, was superfluous; we already know how to prevent parent – to – child transmission of HIV and, even in the event of a failure of our knowledge, the HIV infection is treatable. However, previous research had suggested that people with two copies of CCR5-32 have an increased risk of being infected with other viruses. This raised fears that gene editing is not just useless, but harmful.

Two researchers from the University of California, Berkeley (Xinzhu Wei and Rasmus Nielsen) decided to check if that was the case. To do this, they relied on the UK Biobank, an ambitious effort to collect genetic information and monitor the health status of half a million British residents. All data are not yet available, but Wei and Nielsen were able to consult the CCR5 genotype of more than 400,000 individuals. While the CCR5The mutation 32 is rare in the British population, which allowed the study to collect data to thousands of people.

An early death

We do not know for which diseases CCR5-Δ32 increases are sensitive, so the researchers simply looked at mortality from all causes. It would also include non-infectious problems, for example if the mutation changed the frequency of autoimmune problems.

The results were spectacular: "Cumulative death rates between 32 and 32 years are about 21% higher before age 76 than other genotypes." In other words, people with two copies of the mutation were 20% less likely to reach the age limit of 76 years. Risks also seemed to increase with age, the largest difference being observed in people with two copies of the mutation at age 74, while the death rate was 25% higher in people with the disease. CCR5-32 mutation.

People with a normal and a CCR5Version 32 of the gene also has significant protection against HIV infections. And, in this study, their mortality rate was indistinguishable from two undamaged copies of the gene.

The authors also examined the dynamics of CCR5-32 mutation within the population, looking for signs of evolutionary changes in its frequency. This badysis produces a number corresponding approximately to the mortality data. Why does not HIV create some pressure to increase the frequency of this mutation? Two reasons: drug treatments now allow people living with HIV to survive, and the frequency of HIV infection in the UK is only about 0.16%, which is too low to have strong influence on genetics.

To get an idea of ​​what could be causing people with two copies of CCR5-Δ32 died to die early, the researchers looked for other health effects badociated with the mutation. And they found a lot. Even after correcting for the fact that they were multiple tests (which increases the risk of misleading badociations), they found many health problems related to CCR5-Δ32. It should not be a shock for something central to immune function.

The clear message of this badysis is that the adoption of CCR5-Δ32 as a form of protection against HIV is not something we should do lightly. While this may be a reasonable approach for someone already treated with both leukemia and HIV infection, it is clear that premature gene editing has left its recipients at risk for health. for life.

Nature Medicine, 2019. DOI: 10.1038 / s41591-019-0459-6 (About DOIs).