The news out of March’s annual big retrovirus conference was extremely exciting.
Xu Yu, M.D., of the Ragon Institute (a research partnership among Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University), presented findings at CROI 2021 about “elite controllers”: those seemingly magical folks with HIV who suppress HIV naturally, without meds.
As she recounted, at least two such controllers suppressed their HIV so thoroughly that active virus could not be found in their systems at all, not even to the very low levels found in the others. (One of those two—Loreen Willenberg, 66, of Sacramento, California, who has thrown herself into advocacy around the issue—is a former writer for TheBody.)
Among all the controllers, Yu and her colleagues found that their HIV was “hiding out” in the so-called “gene deserts” of the human genome—our body’s genetic-material junkyard, basically—far from cells that might act as host cells for HIV to invade and take over as part of its dastardly replication process (which is blocked in most people with HIV via our HIV meds).
“There was functional HIV virus in there,” Yu told TheBody, “but with nothing to latch on to. These people have a unique immune response.” But the big question in the field is why? What part of the body’s complex immune system is beating out HIV in these lucky elite controllers?
And right now, the answer in the field is, as Yu put it, “We don’t know.” Even in this small group, she says, which parts of the immune system are doing this incredible work could vary from person to person.
But there’s one thing the field is unanimous about: The findings are thrilling. “They give us a blueprint of what a functional cure could look like,” said Yu. “We used to think you had to eradicate every single intact HIV virus” to get to a cure, but these findings suggest that HIV could “just sit there in the genome desert” and do no harm.
Of course, this was not the first study about elite controllers. They’ve been identified and studied for years, all toward the goal of figuring out how they naturally control HIV—and if that process could then be applied to a cure therapy. In fact, dozens of such therapy trials are in very early stages in the U.S. and elsewhere, most of them focused on creating a vaccine that would infuse people living with HIV with superpower T cells.
Such T cells would “be able to target vulnerable parts of HIV, indefinitely, with maximal firepower—that’s our holy grail.” Those are the words of Steven Deeks, M.D., at the University of California, San Francisco, who is among the researchers who’ve been studying elite controllers for years.
However, he said, superpower T cells alone likely won’t be enough. “We also need vaccine boosters that stimulate generalized immune inflammation and rev up the immune response.” He said that both his and many other researchers’ studies in this direction, including those at HIV pharma giant Gilead, are all based on work that Harvard’s Dan Barouch, M.D., Ph.D., conducted in monkeys nearly a decade ago.
The new approach is called “block and lock,” because HIV is essentially blocked from entering host cells, then locked into gene deserts where it doesn’t die, but lives forever out of harm’s way.
There’s just one catch: For researchers to continue down this path, they need folks with HIV to come forward for studies. And that presents multiple challenges.
For one thing, most folks with HIV in rich countries are doing just fine on current HIV meds. Eventually, such studies will need folks with HIV to come off those meds for varying lengths of time to see what happens in bodies that have been given an immune boost but are then deprived of conventional HIV therapy. And, as we’ve already seen in such trials, that presents the risk that people will go from that much-desired and encouraged state of undetectable to, well, detectable. That not only means letting HIV circulate again, with all its potential health risks, but no longer being untransmittable to sex partners as well.
And that’s a lot for the average person with HIV circa 2021 to wrap their heads around, especially after we’ve been inundated with the U=U (undetectable equals untransmittable) mantra the past several years now. As someone with HIV who is very pro-science and pro-studies, it’s a lot for me to wrap my head around. Would I really want to do this in order to play a small role in finding a theoretical cure?
For folks with HIV, the prospect of joining such trials “is all risk and no benefit at this point, totally altruistic, so people really need to do their homework,” says Jeff Taylor of Palm Springs, California, himself living with HIV. He heads the HIV + Aging Research Project and works closely with fellow activist Lynda Dee (of AIDS Action Baltimore) and Karine Dubé, D.P.H. (of the University of North Carolina) on research looking into what folks with HIV would need to know or have, and what they’d tolerate, in exchange for participating in such research.
Studies in recent years that Dubé, Taylor, and Dee have coauthored have included such findings as:
- Roughly two-thirds of people with HIV were “somewhat willing” to stop their HIV meds for cure research. Personal health and broader social benefit were motivators to participating, while concerns about risk to personal health were impediments. (Duh.)
- Subgroups who were less willing to participate than others included women, Black people, Hispanics, the lowest-income individuals, long-term survivors, and those who perceived themselves as “very healthy.”
- Potential study volunteers said they needed more information and education about the potential risks of such trials, and also, interestingly, seemed to have a greater awareness of both risks and benefits of participating than did study researchers, policymakers, and bioethicists. Some, not all, people with HIV said there was no limit to how much risk they would take to help be part of a cure.
Based on these findings, said Dee, “We need to make sure people [with HIV who participate in such trials] know what they’re getting into. It would be illegal to make these studies sound nicer than they are.”
Taylor agreed: “If these trials sound scary because they involve going off your meds, it’s because they are scary. You need to give people a really clear-eyed assessment. Trials [seeking to recruit them] must have them watch videos and completely revamp the informed consent process.”
But Dee also added that she thinks current trials using the “block and lock” approach sound safer than older cure-oriented trials using the so-called “shock and kill” approach, in which repurposed cancer drugs are used to try to flush latent HIV out of the body’s hidden reservoirs, then zap it dead with HIV meds.
“Block and lock may be far away from coming to fruition,” said Dee, “but it makes so much more sense to try to keep HIV tapped down instead of trying to wake it up with chemo-like agents.”
One thing is certain going forward with trials, said Dubé: “We need an approach that understands and centers the patient/participant perspective, what level of risk they’re willing to take.” That’s why, she says, studies into potential participant attitudes, such as those mentioned above, are as important as the actual cure trials themselves.
Right now, this database of cure trials is maintained by Richard Jefferys, the Basic Science, Vaccines, and Cure Project director at Treatment Action Group. (He is reachable at email@example.com.) However, at the moment, it does not appear as if a more average-person-with-HIV-friendly guide to potential trials is available online. Taylor says something like that may be forthcoming in the months ahead.
Additionally, Yu said, “At the Ragon Institute, we have a confidential inbox, firstname.lastname@example.org, and our clinical team members will get in touch very soon after receiving the emails. One can also call the phone line anytime at 857-268-7257, Monday through Friday, 8:30 a.m. to 5 p.m., to reach one of our clinical team members to discuss possible participation in our studies on elite controllers or long-term HIV-medication–treated individuals.”
Yu also noted that her Boston-based team collaborates closely with Deeks’ team in San Francisco, giving opportunities for trial participation on both coasts. And she stressed that, at this point, her team’s studies are merely analyzing blood samples from folks with HIV like me who’ve been on HIV meds for a long time. No going off meds is necessary at this point.
Who Would Benefit From a Cure?
Another question raised by the race for a functional HIV cure is: Who would most profit? Currently, HIV meds, notoriously high-priced and meant to be taken nonstop for a lifetime, bring in nearly $30 billion annually for drugmakers, with most of that market being in North America.
“HIV meds are like an ATM machine for drug companies,” admitted Deeks—but he doesn’t think that’ll stop drugmakers from partaking in the race to a cure. “There’s the competitive instinct. Companies who’ve done well in terms of treating HIV, including Gilead, have a genuine desire to be part of the end game.”
It also should be noted that Gilead has not exactly done shabbily by coming up with the breakthrough therapies that cure hepatitis C; those drugs have netted the company untold billions of dollars. [Editor's note: Gilead is one of several ad sponsors on TheBody, but as with all ad sponsors, we have complete editorial independence in determining what stories we pursue and how we cover them.]
Dee agreed with Deeks’ assessment. “There’s always going to be some monstrous new bug [to develop treatments for] besides HIV,” she said. “And with HIV, everyone wants to be the one to find the cure and get the prize—ego motivates people.”
And Taylor pointed out that the HIV meds market is slowing in rich countries as pre-exposure prophylaxis (PrEP) becomes more widely available and new HIV infections taper off.
Precisely because many people with HIV in rich countries are fine with living the rest of their lives on easy-to-take HIV meds is why an actual HIV cure might most benefit poor countries. Globally, even though access to HIV treatment has expanded dramatically the past 20 years, more than 30% of all those living with HIV still had not accessed treatment by the end of 2019, according to HIV.gov.
“There are still a lot of people in the world who don’t have lifelong access to HIV meds” and could benefit from a therapeutic vaccine, said Deeks. “The money is there to help us explore this potential, from places like the Gates Foundation, amfAR, and the NIH,” he said. “But we in the academic world need to provide evidence that this is feasible, so the pharma industry can take things across the finish line.”
Which, of course, brings us back to the question of whether we folks with HIV will put our own bodies on the line in studies. Will we?
As for me, guess what? I’ve decided to take the first step. After all, at this point, they only want a blood sample—not a commitment to going off meds. So I’m awaiting my marching orders from Xu’s Ragon Institute. I’ll keep you posted!