How Three People With HIV Became Virus-Free Without Drugs

How Three People With HIV Became Virus-Free Without Drugs

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You’re not entirely human.

Our DNA contains roughly 100,000 pieces of viral DNA, totaling 8 percent of our entire genome. Most are ancient relics from long-forgotten invasions; but to HIV patients, the viral attacks are very real and entirely prescient to every moment of their lives.

HIV is the virus that causes AIDS—the horrifying disease that cruelly eats away at the immune system. As a “retrovirus,” the virus inserts its own genetic material into a cell’s DNA, and hijacks the cell’s own protein-making machinery to spew out copies of itself. It’s the ultimate parasite.

An HIV diagnosis in the 80s was a death sentence; nowadays, thanks to combination therapy—undoubtedly one of medicine’s brightest triumphs—the virus can be kept at bay. That is, until it mutates, evades the drugs, propagates, and strikes again. That’s why doctors never say an HIV patient is “cured,” even if the viral load is undetectable in the blood.

Except for one. Dubbed the “Berlin Patient,” Timothy Ray Brown, an HIV-positive cancer patient, received a total blood stem cell transplant to treat his aggressive blood cancer back in 2008. He came out of the surgery not just free of cancer—but also free of HIV.

Now, two new cases suggest Brown isn’t a medical unicorn. One study, published Tuesday in Nature, followed an HIV-positive patient with Hodgkin’s lymphoma, a white blood cell cancer, for over two years after a bone marrow transplant. The “London patient” remained virus-free for 18 months after quitting his anti-HIV drugs, making him the second person ever to beat back 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 using drugs. He stopped anti-virals in November 2018—and doctors only found traces of the virus’s genetic material, even when using a myriad of ultra-sensitive techniques.

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

Is There a Cure on the Horizon?

Sadly, no. Stem cell transplant, often in the form of a bone marrow transplant, is swapping one evil out with another. The dangerous surgery requires extensive immunosuppression afterwards and is far too intensive as an everyday treatment, especially because most HIV cases can be managed with antiviral therapy.

Why Did Stem Cell Transplants Treat HIV, Anyways?

The common denominator among the three is that they all received blood stem cell transplants for blood cancer. Warding off HIV was almost a lucky side-effect.

I say “almost” because the type of stem cells the patients received were different than their own. If you picture an HIV virus as an Amazon delivery box, the box needs to dock to the recipient–the cell’s outer surface—before the virus injects its DNA cargo. The docking process involves a bunch of molecules, but CCR5 is a critical one. For roughly 50 percent of all HIV virus strains, CCR5 is absolutely necessary for the virus to get into a type of immune cell called the T cell and kick off its reproduction.

No CCR5, no HIV swarm, no AIDS.

If CCR5 sounds familiar, that may be because it was the target in the CRISPR baby scandal, in which a rogue Chinese scientist edited the receptor in an ill-fated attempt to make a pair of twins immune to HIV (he botched it).

As it happens, roughly 10 percent of northern Europeans carry a mutation in their CCR5 that make them naturally resistant to HIV. The mutant, CCR5 Δ32, lacks a key component that prevents HIV from docking.

Here’s the key: all three seemingly “cured” patients received stem cells from matching donors who naturally had the CCR5 Δ32 to treat their cancer. Once settled into their new hosts, blood stem cells activated and essentially repopulated the entire blood system—immune cells included—with the HIV-resistant super-cells. Hence, bye bye virus.

But Are Mutant Stem Cells Really the Cure?

Here’s where the story gets complicated.

In theory—and it is a good one—lack of full-on CCR5 is why the patients were able to beat back HIV even after withdrawing their anti-viral meds.

But other factors could be at play. Back in the late 2000s, Brown underwent extensive full-body radiation to eradicate his cancerous cells, and received two bone marrow transplants. To ward off his body rejecting the cells, he took extremely harsh immunosuppressants that are no longer on the market because of their toxicity. The turmoil nearly killed him.

Because Brown’s immune system was almost completely destroyed and rebuilt, it led scientists to wonder if near-death was necessary to reboot the body and make it free of HIV.

Happily, the two new cases suggest it’s not. Although the two patients did receive chemotherapy for their cancer, the drugs specifically targeted their blood cells to clear them out and “make way” for the new transplant population.

Yet between Brown and the London patient, others have tried replicating the process. But everyone failed, in that the virus came back after withdrawing anti-viral drugs.

Scientists aren’t completely sure why they failed. One theory is that the source of blood stem cells matters, in the sense that grafted cells need to induce an immune response called graft-versus-host.

As the name implies, here the new cells viciously attack the host—something that doctors usually try to avoid. But in this case, the immune attack may be responsible for wiping out the last HIV-infected T cells, the “HIV reservoir,” allowing the host’s immune system to repopulate with a clean slate.

Complicating things even more, a small trial transplanting cell with normal CCR5 into HIV-positive blood cancer patients also found that the body was able to fight back the HIV onslaught—up to 88 months in one patient. Because immunosuppressants both limit the graft-versus-host/HIV attack and prevent HIV from infecting new cells, the authors suggest that time and dosage of these drugs could be essential to success.

One more ingredient further complicates the biological soup: only about half of HIV strains use CCR5 to enter cells. Other types, such as X4, rely on other proteins for entry. With CCR5 gone, these alternate strains could take over the body, perhaps more viciously without competition from their brethren.

So the New Patients Don’t Matter?

Yes, they do. The London patient is the first since Brown to live without detectable HIV load for over a year. This suggests that Brown isn’t a fluke—CCR5 is absolutely a good treatment target for further investigation.

That’s not to say the two patients are cured. Because HIV is currently only manageable, scientists don’t yet have a good definition of “cured.” Brown, now 12 years free of HIV, is by consensus the only one that fits the bill. The two new cases, though promising, are still considered in long-term remission.

As of now there are no accepted standards on how long a patient needs to be HIV-free before he is considered cured. What’s more, there are multiple ways to detect HIV load in the body—the Düsseldorf patient, for example, showed low signals of the virus using ultrasensitive tests. Whether the detected bits are enough to launch another HIV assault is anyone’s guess.

But the two new proof-of-concepts jolt the HIV-research sphere into a new era of hope with a promise: the disease, affecting 37 million people worldwide, can be cured.

What Next?

More cases may be soon to come.

The two cases were part of the IciStem program, a European collaboration that guides investigations into using stem cell transplantation as a cure for HIV. As of now, they have over 22,000 donors with the beneficial CCR5 Δ32 mutation, with 39 HIV-positive patients who have received transplants. More cases will build stronger evidence that the approach works.

However, stem cell transplants are obviously not practical as an everyday treatment option. But biotech companies are already actively pursuing CCR5-based leads in a two-pronged approach: one, attack the HIV reservoir of cells; two, supply the body with brand 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 edited CCR5 from extracted blood cells before infusing them back into the body—a sort of CAR-T for HIV. The number of edited cells weren’t enough to beat back HIV, but did clear out a large pool of the virus before it bounced back. With the advent of CRISPR making the necessary edits more efficient, more trials are already in the works.

Other efforts, expertly summarized by the New York Times, include making stem cells resistant to HIV—acting as a lifelong well of immune cells resistant to the virus—or using antibodies against CCR5.

Whatever the treatment, any therapy that targets CCR5 also has to consider this: deletion of the gene in the brain has cognitive effects, in that it enhances cognition (in mice) and improves brain recovery after stroke. For side effects, these are pretty awesome. But they also highlight just how little we still know about how the gene works outside the immune system.

Final Takeaway?

Despite all the complexities, these two promising cases add hope to an oft-beaten research community. Dr. Annemarie Wensing at the University Medical Center Utrecht summarized it well: “This will inspire people that a cure is not a dream. It’s reachable.”

Image Credit: Kateryna Kon / Shutterstock.com

Think.intellect

via Singularity Hub https://meson.in/2EASxAx

March 10, 2019 at 11:01PM

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