During the 1980s, there was widespread fear of the AIDS epidemic that was sweeping Northern Europe and America. I was a young child at the time and don’t remember much about it, but by the 1990s my fellow teenagers and I were certainly very well aware of this terrible disease and the importance of safe sexual practices. It seems rather strange (and alarming) to me that there is a whole generation of people here who have grown up without that spectre hanging over them. Modern treatment for HIV, the virus that causes AIDS, has transformed it from a certain death sentence to a something that, with combination antiviral therapy, can be lived with for (so far) a normal lifespan. This is a scientific triumph. The story in less wealthy countries of the world, particularly the ongoing pandemic in Africa, is far less rosy, with a million people worldwide dying of the disease last year.

During those turbulent times, stories emerged of people – usually European or American homosexual men, who were the main victims among those populations at that time – who never got the disease, despite repeated exposure. Of course, it’s usually the case that there are resistant individuals to diseases in human populations, but this was a brand new disease spreading, and mutating, incredibly rapidly. Whatever was different about their genes, it was present at their birth, long before the pandemic started. What was this genetic change that meant they could survive what was then unsurvivable, and even not to catch it all? 

Many of these people volunteered themselves for medical research, and the mutation was identified in 1996 in a Cell paper. This followed on from extensive research into the mechanism of HIV infection. Viruses enter living cells and hijack the cell’s machinery to make more copies of themselves. HIV infects T-cells, which are cells of the immune system, hence why it is so hard for your body to detect and destroy the virus, and why, eventually, the immune system starts failing and you get AIDS. Your cells have many “receptors” on them that bind chemical signals, called ligands, causing activation within the cell of a whole suite of appropriate responses. (For example, the hormone adrenaline binds the adrenergic receptor, leading to increased breakdown of muscle energy stores). HIV exploits this system by binding a receptor called CD4 on a particular class of T-cells that possess it, to gain entry to the cell, but it also requires activation by a co-receptor, either CCR5 or CXCR4. Essentially, when HIV binds both these receptors, it causes the viral membrane to fuse with the cell membrane and the virus is internalised. [See figure below]. It was in the gene for this co-receptor that these resistant individuals possessed a mutation.

HIV_attachment
Attachment of HIV to a CD4+ T-helper cell: 1) the gp120 viral protein attaches to CD4. 2) gp120 variable loop attaches to a coreceptor, either CCR5 or CXCR4. 3) HIV enters the cell. National Institutes of Health, from Wikipedia.

The gene in which the mutation is present is called CCR5; it is a chemokine receptor. Chemokines are signals, similar to hormones, that are specifically involved in immune responses. The binding of chemokines to receptors attracts the T-cells to tissues and organs in response to an infection. The mutation is called delta32: what this means is that a 32 base pair section of the DNA has undergone a deletion. This deletion introduces a premature “stop” signal into the coding sequence. This results in the CCR5 co-receptor simply not being made, and so it isn’t present on the surface of the T-cell. HIV therefore cannot gain entry to the cell and cause infection. If you have two copies of this mutation, you are likely to be able to resist HIV infection (it protects against HIV-1, one of the main subtypes of the virus). Even if you have only one copy, you are less likely to be infected, and the disease progress will be slower if you are. Surprisingly, the lack of CCR5 doesn’t seem to have any deleterious effects (but more on that later…). I say “surprisingly” because usually if you lose something as critical as a receptor for a key immune signalling molecule, you expect problems.

But where did this mutation come from? It quickly became apparent that this wasn’t a brand new mutation, nor was it a particularly rare one. In fact, an early study in 1998 sampled DNA from various populations and concluded that the CCR5-delta32 gene variant, or allele, was present at rates of between 0-14% in Eurasian populations, but virtually absent in African, Native American, Asian and Middle Eastern groups. (It seems particularly cruel that a gene which could be so beneficial to Africans is mostly present in Europeans). They estimated, very broadly, that the mutation arose around 700 years ago: combined with the frequency and distinct geographic distribution, this suggested that it arose from a single mutation and was strongly selected for, spreading rapidly. This in turn must mean that this mutation confers some advantage other than HIV resistance, because HIV didn’t infect humans until the mid 20th century.

So what was this mysterious force of natural selection that meant this gene mutation was so strongly selected for in Europe? It seems fairly obvious, given the immune system role of the gene, that it is probably something to do with resistance to another disease. But which one? Well, when you think back to what was happening around 700 years ago in Europe, there is one really nasty disease that literally screams out at you: plague. Specifically, bubonic plague, the infamous Black Death that spread in the 1340s throughout Europe, killing an estimated 25-40% of the entire population of the continent. It was one of the most devastating pandemics in human history. Other later plague epidemics swept through the continent at regular intervals, killing huge numbers of people again. (It’s still around today, but fortunately there are only a few thousand cases a year, and we have antibiotics to treat it). The plague bacterium, Yersinia pestis, has a very high mortality rate, so anything that would give you even a slight advantage in terms of resisting infection, or surviving once infected, would be highly selected for.

It’s a really seductive idea: in fact, in researching for this blog I’ve seen several sources (including scientific ones) cite it as if it was proven, which it isn’t. Plague exerts a hold on the European psyche. No other disease has killed such a large proportion of people in Europe in such a short period as the bubonic plague did during the Black Death. What better than to think that this terrible disease, which caused such immense death and suffering, led to the selection and spread of a mutation that would allow the descendants of those who survived to avoid the modern scourge of HIV? I have to say, I thought “Wow! Amazing!” when I first heard the idea, but then I also thought, “But bacteria and viruses have completely different modes of infection…how is this going to help?”

Well, it turns out that the real culprit is probably another disease. One that used to terrify people as surely as AIDS once terrified Europeans and still stalks much of the world, one that has similarly been almost forgotten. A disease that has been with us since before the dawn of agriculture; a scourge for centuries that killed millions upon millions of people: in the 20th century alone, it killed nearly half a billion people. It’s a virus with an extreme mortality rate that can be anything between 20-60% (usually around 30%) – and that rises to over 80% in children. This is important – these are people who die before they are able to reproduce. Any mutation that would confer resistance to this terrible disease would undergo extremely strong evolutionary selection, as has been seen for the CCR5-delta32 mutation. The disease was sometimes called the Red Plague in medieval times. We know it as smallpox, and it was eradicated completely by vaccination in 1977. (Beware there are distressing photos at that Wikipedia link).

Smallpox didn’t arise 700 years ago, but it was rife and deadly at the time that this chance mutation in CCR5 appeared. As mentioned before, it was particularly dangerous to children, and in populations that had frequent epidemics, essentially all surviving adults were immune, wtih nearly all children in Europe, where the mutation arose, contracting the disease by the age of 10. Although the Black Death killed a huge amount of Europeans in a short time, the cumulative number of deaths during the last 700 years from smallpox was greater than that from plague, and, unlike plague, smallpox has a disproportionate effect on young people. At least one analysis has shown that plague outbreaks didn’t provide enough of a selective pressure to explain the spread of the CCR5 delta32 mutation, but smallpox does. It’s likely the mutation arose somewhat earlier than 700 years ago in northern Europe, and was spread by Viking dispersal further south. Indeed, Scandinavian populations were hit hard by smallpox epidemics, which may explain why the frequency of this mutation is higher in those with northern European ancestry.

Importantly, this explanation for the mutation also makes more sense from an immunological perspective. Variola major virus, which causes smallpox, is (aptly) a member of the poxvirus family. These use chemokine receptors to enter white blood cells, similar to HIV, so this makes it far more biologically plausible that a mutation which removes the CCR5 coreceptor will confer resistance against both diseases. It’s a great explanation….but it still might not be true. There’s no direct proof that possessing this mutation confers smallpox resistance, and of course it’s true that smallpox didn’t just affect Europeans but the entire world. In this respect, it’s important to realise, however, that the diseases won’t have caused the mutation: this, like any mutation, occurred by random chance – it just so happened to be in a population in northern Europe. However, once the mutation was present, the presence of a disease it coincidentally happened to confer resistance to would have made people carrying it more likely to survive. I personally find the smallpox data fairly convincing, although there’s not much of it, but it’s entirely possible it was some other, unknown disease or diseases that the mutation protected against, which may explain at least initially how it spread. Moreover, DNA samples from earlier burials indicate that CCR5delta32 may be older than we initially thought. Its origins remain, for now, a tantalising enigma.

What now for the CCR5delta32 mutation? It remained under strong selective pressure under smallpox was eliminated – now it is being selected for again with respect to HIV resistance, but it’s also provided a potential therapeutic target. Researchers are now trying to knockdown the activity of the CCR5 receptor, or the gene that codes for it, in people that don’t possess the mutation, to try and treat HIV infection. The receptor is a member of a large family of receptors called the G-protein coupled receptors, which are anyway major drug targets (e.g. for asthma and heart disease) so the research community does have familiarity with that type of approach. Receptor antagonists are in pre-clinical trials, and gene editing CCR5 is also a possibility (see e.g. here). The difficulty of making a vaccine against a virus that mutates so rapidly makes treatment options that much more important.

Will this wonderful, lucky mutation continue to spread throughout the human population? As long as there is a strong selective pressure such as HIV, then yes. But it may not be without its downsides. Our body has evolved lots of redundancies, but I’d be suspicious that deleting an important immune receptor would come without any downsides. One of those may be an increased risk or severity of certain autoimmune disorders, notably multiple sclerosis. This may also at least partially explain the higher incidence of MS in northern European populations, particularly those areas colonised by, you guessed it, the Vikings. Even if this were the case though, it’s clear that, in pure terms of natural selection, the advantage of possessing even just one copy of the variant far outweigh the disadvantages.

Featured image:

Scanning electron micrograph of an HIV infected H9 T cell. By NIAID. https://commons.wikimedia.org/w/index.php?curid=39933233

 

References

Galvani & Slatkin, 2003. Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele. PNAS, Vol.100 No.25,  pages 15276–1527, doi: 10.1073/pnas.2435085100

Liu et al, 1996. Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection. Cell, Volume 86, Issue 3, 9 August 1996, Pages 367-377  https://doi.org/10.1016/S0092-8674(00)80110-5

Stephens et al, 1998. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet. 1998 Jun; 62(6): 1507–1515.
doi: 10.1086/301867

 

 

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