How three people living with HIV became drug free

You are not entirely human.

Our DNA contains about 100,000 pieces of viral DNA, or 8% of our entire genome. Most are ancient relics of forgotten invasions; but for HIV-positive patients, viral attacks are very real and totally precocious at every moment of their lives.

HIV is the virus that causes AIDS – the horrible disease that is eating away at the immune system. As a "retrovirus", the virus inserts its own genetic material into the DNA of a cell and diverts the cell's protein production mechanism to make copies of itself. It is the ultimate parasite.

An HIV diagnosis in the 1980s was a death sentence; Nowadays, thanks to combination therapy – undoubtedly one of the most brilliant triumphs of medicine – the virus can be kept at bay. That is to say, until it mutates, avoids drugs, spreads and strikes again. This is the reason why doctors never say that an HIV-positive patient is "cured", even if the viral load is undetectable in the blood.

Except one. Nicknamed the "Berlin Patient", Timothy Ray Brown, a patient with an HIV-positive cancer, received a whole blood stem cell transplant to treat his aggressive blood cancer in 2008. He came out of the clinic in December. operation not only of cancer, but also of HIV.

Two new cases suggest that Brown is not a medical unicorn. A study, published Tuesday in Naturefollowed an HIV-positive patient with Hodgkin's lymphoma, a cancer of the white blood cells, for more than two years after a bone marrow transplant. The "London patient" remained virus-free for 18 months after he stopped taking anti-HIV drugs, making him the second person to fight off the virus without drugs.

The other, presented at the Conference on Retroviruses and Opportunistic Infections in Washington, also received a stem cell transplant to treat his leukemia while controlling his HIV load through medication. He stopped antivirals in November 2018 – and doctors found only traces of the virus's genetic material, even when he used a myriad of ultra-sensitive techniques.

Does this mean that a cure for HIV is in sight? Here is what you need to know.

Is there a cure on the horizon?

Unfortunately no. Stem cell transplantation, often in the form of a bone marrow transplant, involves exchanging one harm with another. Unsafe surgery then requires significant immunosuppression and is far too intensive for daily treatment, especially since most HIV cases can be managed with antiviral therapy.

Why did stem cell transplants treat HIV anyway?

The common denominator between the three is that they all received a blood stem cell transplant for blood cancer. Protecting yourself from HIV was almost a lucky side effect.

I say "almost" because the type of stem cells that patients received was different from theirs. If you represent an HIV virus as an Amazon delivery box, it must be anchored to the recipient – the outer surface of the cell – before the virus injects its DNA cargo. The docking process involves a bunch of molecules, but CCR5 is a critical element. For about 50% of all strains of the HIV virus, CCR5 is absolutely necessary for the virus to enter a type of immune cell called T cell and begin its reproduction.

No CCR5, no swarm of HIV, no AIDS.

If CCR5 sounds familiar to you, it may be because it was the target of the CRISPR baby scandal, in which a dishonest Chinese scientist edited the receiver for the unfortunate purpose of making a pair of twins immune. against HIV (he has botched it).

In fact, about 10% of northern Europeans carry a mutation in their CCR5 that makes them naturally resistant to HIV. The mutant, CCR5 Δ32, lacks a key component that prevents HIV from clinging.

Here is the key: the three apparently "cured" patients received identical donor stem cells that naturally had CCR5 Δ32 to treat their cancer. Once installed in their new hosts, the blood stem cells activated and essentially repopulated the complete blood system – including immune cells – with the HIV-resistant super-cells. Therefore, bye bye virus.

But are mutant stem cells really the cure?

It is here that the story gets complicated.

In theory, and that is a good one – the complete lack of CCR5 is the reason why patients have been able to beat HIV even after the withdrawal of their anti-viral drugs.

But other factors may be at play. In the late 2000s, Brown suffered complete whole body radiation to eradicate his cancer cells and received two bone marrow transplants. To prevent his body from rejecting the cells, he took extremely hard immunosuppressants that are no longer on the market because of their toxicity. The turmoil almost killed him.

Because Brown's immune system was almost completely destroyed and rebuilt, scientists wondered if imminent death was needed to reboot the body and get rid of HIV.

Fortunately, the two new cases suggest that this is not the case. Although both patients received chemotherapy for their cancer, the drugs specifically targeted their blood cells to eliminate them and "give way" to the new population of transplant recipients.

Yet between Brown and the London patient, others have tried to replicate the process. But everyone failed because the virus came back after the withdrawal of antiviral drugs.

Scientists are not sure why they failed. One theory is that the source of blood stem cells is important, in that grafted cells need of induce an immune response called graft versus host.

As the name suggests, the new cells are violently attacking the host, which doctors usually try to avoid. But in this case, the immune attack may be responsible for eliminating the last HIV-infected T cells, the "HIV reservoir," allowing the host's immune system to repopulate with a clean slate.

To complicate things even more, a small test of cell transplant with normal CCR5 in patients with HIV-infected blood cancer also revealed that the body was able to withstand the attack of HIV – up to 88 months in a patient. Since immunosuppressive drugs limit both the graft-versus-host-HIV response and prevent HIV from infecting new cells, the authors suggest that the time and dosage of these drugs could be critical to success.

Another ingredient complicates biological soup even more: only about half of all HIV strains use CCR5 to enter the cells. Other types, such as X4, depend on other proteins for their input. With CCR5 gone, these alternative strains could take the body, perhaps more badly without the competition of their brethren.

So new patients do not matter anymore?

Yes, they do it. The London patient is the first since Brown to live without detectable HIV load for more than a year. This suggests that Brown is no coincidence: CCR5 is a good target of treatment for subsequent investigations.

This does not mean that both patients are cured. Since HIV is currently manageable, scientists do not yet have a good definition of "cured". Brown, who is now 12 years old without HIV, is by consensus the only one suitable. The two new cases, although promising, are still considered in long-term remission.

For the moment, there are no accepted standards on how long a patient should be free of HIV before being considered cured. In addition, there are many ways to detect the burden of HIV in the body: the patient from Düsseldorf, for example, showed low signals from the virus using ultrasensitive tests. It is not known if the bits detected are sufficient to launch another assault against HIV.

But the two new proofs of concept are shifting the sphere of HIV research into a new era of hope full of promise: the disease, which affects 37 million people around the world, can to be healed.

And then?

More cases may be coming soon.

Both cases were part of the IciStem program, a European collaboration that directs research on the use of stem cell transplantation to cure HIV. To date, they have more than 22,000 donors with the CCR5 Δ32 beneficial mutation, including 39 HIV-positive patients who have received transplants. More cases will better demonstrate that the approach works.

However, stem cell transplants are obviously not a daily treatment option. However, biotech companies are already actively seeking CCR5-based solutions in a two-pronged approach: first, to attack the HIV cell pool; second, provide the body with new replacements.

Translation? Use any method to get rid of CCR5 cells in immune cells.

Sangamo, based in California, is perhaps the most prominent player. In one trial, they published CCR5 from extracted blood cells before re-injecting them into the body – a kind of HIV T-CARD. The number of modified cells is not enough to defeat HIV, but eliminates a large amount of viruses before they bounce. With the advent of CRISPR making the necessary editions more efficient, new tests are already underway.

Other efforts, expertly summarized by the New York Times, include the manufacture of HIV-resistant stem cells – acting as a lifeline for immune cells resistant to the virus – or the use of anti-CCR5 antibodies.

Regardless of the treatment, any therapy targeting CCR5 must also take this into account: suppression of the gene in the brain has cognitive effects, in that it improves cognition (in mice) and improves recovery of the brain. brain after stroke. For side effects, these are pretty impressive. But they also point out the lack of knowledge about how the gene works outside the immune system.

Final to take away?

Despite all the complexities, these two promising cases add hope to a community of researchers that is often out of date. Dr. Annemarie Wensing of the Utrecht University Medical Center summed up the situation: "It will make people think that healing is not a dream. It is accessible.

Image credit: Kateryna Kon / Shutterstock.com