June 3, 2019

expert reaction to mutated CCR5 gene and mortality

Researchers, publishing in Nature Medicine, reported that being homozygous for a protective mutation against HIV is associated with increased mortality rate.

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“This study suggests that people who have damaging mutations in both copies of their CCR5 gene may tend to have slightly shorter life spans on average. Such people are highly resistant to HIV infection and even those who only have a mutation in one copy of the gene are partially protected against HIV. However, it seems that not having a working copy of the gene may cause problems in other ways, for example it has been suggested that this might result in increased susceptibility to influenza. Overall, this makes sense. Human beings have CCR5 genes for a reason, even if we do not yet know the fully details about its functionality. Human beings have evolved to possess a CCR5 gene and this means that it must be providing us with some benefit.

“The study highlights the complexity and unpredictability of the effects of altering the genetic code. Here, we might see an advantage in terms of resistance to HIV alongside an adverse effect on overall mortality through mechanisms which are unclear. There are many other examples in medicine where an intervention intended to treat one condition inadvertently causes major unexpected problems elsewhere. This sends us a warning that we should be extremely cautious around the introduction of therapies involving modifying the genetic code, since we can expect that there will be unexpected consequences.”

Prof Robin Lovell-Badge, Group Leader, The Francis Crick Institute, said:

“This is a well worked study, indicating that participants in the UK Biobank project have on average a reduced lifespan if they carry two copies of (are homozygous for) the delta-32 variant of the CCR5 gene. This is a mutation that truncates the protein it encodes, and it has been known for a while that this confers resistance to the HIV virus and AIDS. The virus uses the normal CCR5 protein as a receptor to gain entry into cells of the immune system, but if this was all it did, one might have suspected that the delta-32 mutation might on average increase average lifespan. But clearly CCR5 likely has many other roles, and these are still being discovered. It has roles in the immune system and individuals homozygous for the delta-32 variant are known to be more susceptible to some other viruses, such as West Nile Virus and there is some suggestion that they are also more susceptible to the bad effects of influenza, although this is challenged in other studies. There is also evidence from studies in mice and humans that being homozygous for the delta-32 variant may have a positive effect on some cognitive abilities and to make the brain more robust to the effects of stroke. The CCR5 gene is expressed within the brain, but it is really not clear what its normal function is here, and it is likely that mutations in the gene also have bad effects. The data in the paper from Wei and Nielsen is simply correlative and it does not give any clues as to why those homozygous for the delta-32 variant tend to live not as long as those without it. Moreover, the effect is only apparent in those already fairly old, well beyond usual breeding age, which could explain why the delta-32 variant is so common (it is not going to be selected against).

“All this shows once more that He Jiankui was foolish to choose CCR5 to mutate in his attempts at germline genome editing. We simply do not yet know enough about the gene. Nevertheless, it is impossible to predict if the mutations carried by the twin girls will have any effect. The reduction in lifespan noticed by Wei and Nielsen did not affect all homozygotes – genetic background and environmental influences are likely to play a part. And their study was in the UK, not China where both such influences will be very different.”

Dr Andrew Freedman, Reader in Infectious Diseases / Hon. Consultant Physician, Cardiff University, said:

“This study should act as a stark warning that manipulation of the human genome with the aim of reducing susceptibility to specific diseases is not without considerable risk. While it is clear that the roughly 1% of Caucasian individuals who have two copies of the defective CCR5 gene are protected from HIV, this appears to be at the expense of a significant reduction in overall life expectancy.

“This type of study cannot shed light on the actual mechanism of the increase in mortality, but other studies have indicated that this mutation may reduce protection from other infections such as ‘flu. Further studies will be required to see if these findings can be reproduced, as well as to investigate just how the mutation interferes with immune responses.”

Prof Graham Cooke, NIHR Research Professor, Imperial College London, said:

“These are important findings. Although we know a lot about the CCR5 gene and its role in disease, there is still a lot to be learned. This particular study needs to be repeated, where possible, in other age groups and other populations outside the UK, particularly where other diseases, not just HIV, may contribute to mortality.

“Although this work doesn’t explain why the effect is seen, it does highlight the need to understand mutations in greater detail before we consider creating them medically.”

Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:

“To infect a cell, most circulating strains of HIV hijack a protein, found on the surface of white blood cells, called CCR5. Our genomes contain two copies of the CCR5 gene, and it is well established that those people where both copies of CCR5 are defective are highly resistant to HIV, raising the possibility that it might be possible to prevent or cure HIV infection by genetically engineering a person’s CCR5 gene. Indeed, this was the stated reasoning behind the recent announcement of the gene-edited babies born in China; a proclamation that caused an almost universal uproar – not least because the full impacts of carrying defective CCR5 genes are not fully understood.

“What this study shows is that when both copies of the gene are defective your chances of dying before the age of 76 are increased by over 20%. In other words, these data suggest that any intervention designed to knock out your CCR5 gene, as in the case of the Chinese gene-edited babies, is not without measurable risk of premature death. However, the current study stops short of telling us is why this genetic defect is associated with an early demise.”

* ‘CCR5-Δ32 is deleterious in the homozygous state in humans’ by Wei et al. was published in Nature Medicine on Monday 3^rd June 2019. 

Declared interests

Prof Robin Lovell-Badge: “Robin Lovell-Badge has no conflicts of interest to declare, except he is a member of the WHO panel looking into governance of human genome editing.”    

Dr Andrew Freedman: “No conflicts of interest”

None others received.