Archive for July 2, 2019

CHERUB Investigators and Professors John Frater (Oxford) and Ravi Gupta (Cambridge) in The Guardian about HIV cure

“Fifty years of HIV: how close are we to a cure?”

The Guardian – 2nd July 2019

” It’s half a century since the first known HIV-related death and two patients appear to have been cured of the virus. What does this mean for the 37 million still living with it?”

[…]

“… on 5 March 5 this year, a breakthrough was announced: a team of UK-based researchers had successfully treated a man, identified only as the “London patient”. They declared his HIV in remission for 18 months and counting. The London patient was diagnosed with HIV in 2003, but in 2012 came a second diagnosis: advanced Hodgkin lymphoma, a cancer of the immune system. The only treatment left was intense chemotherapy, followed by a bone marrow transplant containing the stem cells required to rebuild his hollowed-out immune system. That transplant presented an opportunity to treat the London patient’s HIV, too.

Scientists selected a donor with a rare genetic mutation that grants resistance to HIV. When HIV infects its target cell, it does so via a protein on the cell’s surface called CCR5. But the genetic mutation changes the shape of the CCR5, leaving HIV with nothing to latch on to. The London patient’s immune system was rebuilt with HIV-resistant cells – and the virus was eliminated from his blood. “My reaction to the news was: ‘Finally! It’s about time someone succeeded!’” says Dieffenbach. It’s only the second time the procedure has worked: the first was Timothy Ray Brown, sometimes known as the “Berlin patient”, who has now been in remission from HIV for more than 10 years.

But Brown’s treatment was much more brutal: he underwent full body irradiation, and two separate stem cell transplants, each of which poses a risk of death if the graft doesn’t take. The few other patients who have undergone this form of treatment have either died from the cancer’s return, been killed by the transplant, or had their HIV bounce back.

“The Berlin patient left us wondering whether we need to take a patient near to death to cure HIV,” says Professor Ravindra Gupta, who led the London patient’s team. “Now we know you don’t. You can give much less toxic regimens of chemotherapy. And maybe you can get away with less still.” However, he cautions that reducing the harms of the procedure doesn’t equate to making it safe or viable.

First, it is much too dangerous to administer to people receiving antiretroviral treatment who can already live healthy lives. Second, the stem cell transplants bring their own risks: when grafts don’t take, the body rebels, and can even kill the patient. And third, it relies on finding a donor with the CCR5 mutation who is also a blood match for the recipient patient: “It’s incredibly rare to find that combination of factors,” says Gupta.

For Gupta, perhaps the most valuable outcome of the London patient experiment is not the precise procedure they underwent, but the general proof of concept it provides – ie, that targeting CCR5 may lead to an HIV cure: “Gene editing is the most obvious way of extending these findings,” says Gupta.

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In the meantime, many other strategies are under development, and two in particular have made headlines in the last year. The first involves antibodies: Y-shaped proteins produced in response to foreign substances in the blood. 

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The other approach, trialled last year, is known as “kick and kill”: first, you wake up the latent virus, so it reveals itself; then, you attack it.

“Latently infected cells appear identical to uninfected cells, so there is no way [for the body] to distinguish between the two,” says Professor John Frater of the University of Oxford. “But if those cells start to express viral proteins on their surface, they become a target.” The trouble with this method is that to cure someone of HIV, it would need to reactivate almost all the virus, but a kick strong enough to do that without harming the patient hasn’t yet been found. “Our participants are well people,” says Frater, “so our threshold for risk is much lower.” The trial failed.

[…]

Because while HIV is no longer a death sentence in rich countries, it remains a burden. For those without free or affordable healthcare, it’s a significant cost; and when stigma abounds, it can still prevent people from living and loving as they see fit. But it is in poorer countries that the epidemic still rages most fiercely. In 2017, around one million people died of Aids-related illnesses, shattering families and hamstringing the economic potential of nations. And when medications are not taken as prescribed, or only sporadically available, there’s a real risk that drug-resistant HIV might one day rear its head.

For Frater, that’s enough of a reason to keep trying: “A cure should never be taken off the agenda.”

Read the full article in The Guardian.