Exploiting the CCR5 Receptor: Potential Avenue for HIV Cure?

This transcript has been edited for clarity.

Hello. This is Dr Paul Sax from Brigham and Women's Hospital and Harvard Medical School. Today I'd like to discuss a paper that was recently published in Nature Medicine on the CCR5-delta 32 mutation.^[1]

Recall that if a person has two copies of this CCR5-delta 32 mutation (homozygous), then they are essentially uninfectable by HIV, at least HIV that is CCR5-tropic, which is most of the HIV that is transmitted. This was discovered when people evaluated certain individuals who were exposed to HIV multiple times but didn't contract it. It's a very interesting target for drug development.

As a result, it ended up being the target for the drug maraviroc, which is a CCR5 antagonist. It was attractive because people who had two copies of the CCR5-delta 32 mutation actually seemed pretty healthy. Not only that, but the two cases of HIV "cure" (and they probably are cured, not just in remission) involved individuals with hematologic malignancies who underwent stem cell transplantation from donors who had CCR5-delta 32 homozygosity. When their cells regenerated and donor cells were fully in their system, they actually could not be infected. They stopped antiretroviral therapy and have not experienced viral rebound.

Based on these two cases, especially the first one, there has been a lot of interest in exploiting modification of the CCR5 receptor as a way of achieving HIV cure without going through the risks associated with stem cell transplantation. So far, that has included some limited data on the use of something called zinc finger nucleases to sort of snip off the CCR5 receptor. That is an area of research that seems to have stalled somewhat.

More recently, and very controversially, someone in China used gene therapy to modify the CCR5 receptor in embryos to protect the babies from contracting HIV. But the controversy was that they were not really at risk for HIV to begin with. It was an ethically troubling experiment.

Excess Mortality With CCR5 Mutation Homozygosity

This recent paper^[1] looked at a large database of more than 400,000 individuals in Britain for whom there was genetic information, including CCR5 status. The investigators compared the prevalence of the CCR5-delta 32 mutation—the homozygous state, the heterozygous state, and neither—in people aged 41-76 years. They found that, over time, the prevalence of the CCR5 mutation homozygous state declined, and this was consistent with an excess 21% mortality.

With the study's methodology, it can show only associations, not causality. The authors postulate that it might have to do with some evidence that people who have CCR5-delta 32 homozygosity may not handle influenza as well. As you recall, influenza is a more lethal disease in elderly populations. And then it brings back the idea of why do we have this mutation to begin with? It's possible that evolutionarily, having CCR5-delta 32 mutations protected us from some of the lethal infectious diseases of childhood and young adults, particularly smallpox, bacterial dysentery, or even the Black Death.

Is the Risk Worth It?

Where does this leave us? If there is, in fact, the 21% increased lifetime mortality for people who have delta 32 homozygosity versus those who don't or those who are heterozygous, is this still an avenue of HIV cure that we should pursue? I don't really know the answer to that. I will say that my patients are still very interested in HIV cure strategies. They would probably be willing to accept some increased risk if it meant that there was viral eradication or HIV cure. This is clearly going to be an area that is going to require some shared decision-making, because no one thinks that an HIV cure strategy is going to be 100% safe. If it were 100% safe, of course everyone would adopt it. But this latest paper does at least raise the question of whether it will be safe to modify the CCR5 receptor in individuals who are entering, for example, an HIV cure clinical trial.

Thank you very much for listening. I've been reviewing a recent paper published in Nature Medicine, on the possible association between the CCR5-delta 32 mutation and increased mortality.

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