On The Cusp of a Cure

Since the first cases of what would become known as AIDS were reported in June 1981, nearly 700,000 Americans have died due to complications from the disease. Though they might not physically remain with us, their spirits continue to inspire our stories and progress us towards an HIV-free generation.

In the last couple of decades, science has discovered HIV began much earlier than the 1980s, too. Researchers have delivered medications able to suppress the virus to undetectable levels (ultimately saving millions of lives), and has edged closer to finding a cure. But, even as technology becomes more sophisticated, researchers have also discovered that curing — or even stopping — the virus is far more complicated than they had anticipated. HIV can now be suppressed to such low levels that it becomes impossible to transmit to others. With the right combination of antiretroviral drugs, HIV-positive people can keep the virus at bay — allowing them to live long and healthy lives without the fear of death looming over them. But it wasn’t always this way…

The First Anti-HIV Drug

It took the U.S. Food and Drug Administration seven years to approve the first anti-HIV drug, and tens of thousands died in the interim. To combat the rising death rates, public health officials were pressured to give something — anything — to treat those living with HIV. They found it in azidothymidine, also known as AZT, a drug originally developed to fight cancer by inserting itself into the DNA of a cancer cell to stop it from replicating.

When the AIDS crisis was at its height, the pharmaceutical company Burroughs Wellcome found a version of AZT that appeared to block HIV activity in animal cells. A clinical trial of 300 people diagnosed with AIDS compared AZT to a sugar pill. After four months, many of the participants on the sugar pill had died, but AZT helped stabilize those with HIV, and on March 19, 1987, the FDA approved it as the first AIDS medication.

Dr. Anthony Fauci, who has been the director of the National Institute of Allergy and Infectious Diseases since 1984, has played a leading role in the fight against HIV since day one. “For the years… ‘85, ‘86, it was frustrating, but AZT changed things,” he recalls. “There was a degree of optimism when we showed that AZT prolonged the lives of individuals. That optimism was quickly dampened by the fact that, in many of the patients who were treated with AZT — that’s the only drug we had — after a finite period of time, the virus developed resistance against it.”

There are several classes of HIV drugs today, and AZT is still included in many antiretroviral regimens at very low doses. But at the levels it was first prescribed, AZT ate away at a person’s immune system like rat poison. Still, for nearly a decade it was the best option available, as virtually every other additional medication developed to treat HIV proved disappointing.

1996, The Great Suppression

Protease inhibitors were the second class of antiretroviral drugs developed —  with saquinavir and ritonavir approved by the FDA in 1996. Within a couple years, the Centers for Disease Control and Prevention reported that annual AIDS-related deaths plummeted from 50,000 to 18,000 in the United States.

These miracle drugs were proven to prevent viral replication, and when combined with AZT (and later other drugs), were less prone to the development of drug resistance. Fauci remembers the development of highly active antiretroviral therapy as “about as transforming a moment as when we first discovered the virus back in 1983.”

HIV Reservoirs, The Great Barrier

As our ability to suppress viral replication with antiretroviral treatment increased — especially now that people on treatment are achieving undetectable viral loads — it has enabled those living with HIV to have long and healthy lives, as well as prevent transmission. Still, people around the world dream of a cure, or the complete eradication of HIV from a person’s body.

By far, the greatest barrier to reaching that goal is the existence of viral reservoirs where HIV lies dormant, ready to come roaring back and begin replicating again when someone goes off ART or develops drug resistance.

Of course, scientists have tried to outsmart these reservoirs by conceiving new strategies — particularly one called “kick and kill,” in which latency reversing agents “wake” the inactive virus, and antiretroviral medications kill it on the spot. But Fauci worries it isn’t enough. “Decreasing the size of the reservoir doesn’t really get you much,” he explains, because “when you stop therapy… they almost invariably bounce back.”

Is a Cure Even Possible?

In the last decade, reports of people being “cured” of HIV or experiencing years-long viral suppression without medications have captivated the imaginations of both researchers and those living with the virus. The most important of these cases involves Timothy Ray Brown — dubbed the “Berlin Patient” — who was cured after being treated for leukemia with a bone-marrow-supplied stem cell transplant in 2011.

It was later discovered that his donor happened to be part of the one percent of European descendants who appear immune to HIV (likely as a result of their ancestors having survived the Bubonic Plague).

Unfortunately, later efforts to replicate Brown’s results via stem cell transplants have failed. And, as Dr. Warner Greene, director of Gladstone Institute of Virology and Immunology points out, “doing stem cell transplants puts patients at considerable risk.”

Although Timothy Brown remains HIV-negative, David Margolis, the head of Collaboratory of AIDS Researchers for Eradication, has argued, “there are close to 80 million people that have been infected around the globe over the last century. So, one in 80 million [cured] is not great odds.” 

Those odds were raised slightly with the announcement at this year’s International AIDS Society conference that a 9-year-old HIV-positive girl has remained undetectable for eight years, after only receiving 40 weeks of antiretroviral treatment. More good news from South Africa came last year when Science Translation Medicine reported on a group of HIV-positive children with high viral loads who have no symptoms.

Greene believes he has found one way someone could be asymptomatic despite high viral loads. It involves keeping the immune system’s CD4 T cells from killing themselves, which they do in a vain attempt to stop the spread of the virus. These cell deaths trigger the immune system to send even more CD4 T cells, which end up repeating the deadly cycle. But, if you could stop the T cells from committing suicide — even if you didn’t attack the virus itself — Greene believes you could eliminate most of the symptoms of HIV.

Greene has found that the cellular death spiral can be broken by inhibiting an enzyme known as Caspase-1. One highly potent Caspase-1 inhibitor already exists but was sold to a company that appears to have no interest in developing it for HIV treatments. Greene says, because of this, “we have had to revert to creating our own [drug]… at considerable cost, which has slowed [research].”

Other researchers have turned to the promise in gene editing, but Fauci fears that idea may end up being more science fiction than science fact. “From a concept standpoint, gene editing is interesting and can work, but it may not work unless you do other interventions that are going to be dangerous for the patient,” Fauci says. “Just editing a gene without necessarily ablating the rest of the T cells in the body, may not work. It may protect those cells that were edited, but it’s not going to protect those other cells.” Still, he admits, “I like the idea about pursuing research on gene editing.”

But if curing millions of HIV-positive people isn’t possible, what is?

Medication-free Remission

“We’ve not given up entirely on the notion of eradication,” Greene argues, “but I think where the successes and the gains are being made is around the area of being able to reduce and control the virus.”

Fauci goes one step further, suggesting we need to give up on the old notion of an HIV “cure,” and embrace what he calls “ART-free remission.”

“In other words, getting people to the point where you can give them either sustained time off ART or intermittently be able to get them off ART for months, maybe even years at a time,” Fauci says. Even getting a few months of a medication vacation — without the long-term impacts that currently come from treatment interruption — would be a great advantage. But suppressing HIV for years without additional treatment is the ultimate goal. “That’s where a lot of work is going on.”

Whether you call it antiretroviral-free remission or a functional cure, a number of recent findings suggest we could be on the cusp of much longer-acting treatments.

As Fauci’s team at Emory University reported last year in Science, a drug used to treat gut inflammation (Entyvio) produced long-lasting viral remission in monkeys.

“When the animals were released from antiretroviral therapy, they didn’t rebound,” Greene explains. “Actually, they rebounded and then they reestablished a control. Amazing. The Alpha 4 Beta 7 antibody… seems to be somehow arming an immune defense against the virus that keeps it controlled,” even after ART stopped. Human trials with the antibody have already begun.

Earlier this year at the Conference on Retroviruses and Opportunistic Infections, Fauci said the antibody therapy may “teach the immune system to recognize HIV in a way it doesn’t recognize it if it just sees HIV alone. Our job now is to find out just what the nature of that immune response is.” Understanding that could be a game changer — because the difficultly in training the immune system to respond to HIV has hindered both treatment and vaccine efforts.

All Eyes on a Vaccine

For decades, researchers have been seeking another holy grail: an HIV vaccine. But like those searching for a cure, they quickly discovered creating one wouldn’t be easy. Usually vaccines involve introducing small amounts of a virus to our immune system, which develops antibodies to it. But when our immune system encounters even a small amount of HIV, it kicks into the suicidal-death spiral that Greene uncovered.

Still, a vaccine is seen as essential to ending the global HIV epidemic, and several perspective vaccines are currently in clinical trials. They aren’t all aimed at keeping HIV-negative people negative either. Some are evaluating the possibility of utilizing a vaccine to achieve a functional cure.

In a study published in Nature last year, Dr. Hanneke Schuitemaker from Janssen Vaccines reported that when her team combined an investigational vaccine (which was a combo of two other vaccines) with an immune booster and used it to treat HIV-positive monkeys, they not only reached undetectable viral loads, but also saw reduced viral reservoirs and achieved long-term viral remission.

To do that, Schuitemaker explains, “You need to further educate the immune system through vaccination and if you then wake up the latent virus… [it] can be taken out by the immune system.” In collaboration with Dr. Dan Barouch of Beth Israel Deaconess Medical Center, Schuitemaker’s team found that one-third of their test subjects remained virally suppressed for years after the discontinuation of treatment.

The treatment is now being studied on newly HIV-positive people in Phase I/II clinical trials, but Schuitemaker acknowledges they’ll probably end up needing to add additional drugs to the treatment regimen to increase its effectiveness. That fits with what Greene imagines: “some type of cocktail approach, just like we use with therapy, is probably going to wind up being important for the ultimate functional cure or eradication of the virus and of the latent reservoir as well.”

Schuitemaker and Greene also share ethical concerns, pointing out that any potential cure, even one that is just a temporary remission, must be worth the risk of removing people from antiretroviral treatments known to be working.

“We have to have a safe and effective therapy… for subjects that are doing well on antiretroviral therapy,” Greene says. “We can’t put them at high risk to achieve a cure.”