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At a 2019 HIV cure meeting, “elite controller” Loreen Willenberg (right) speaks with Rowena Johnston, research director of amfAR.

amfAR/The Foundation for AIDS Research

How ‘elite controllers’ tame HIV without drugs

A tiny fraction of the 38 million HIV-infected people in the world have what seems like a superpower. Without the help of antiretroviral (ARV) drugs, they keep the AIDS virus at undetectable levels in their blood, sometimes for many years, even though they still have HIV genes woven into their chromosomes. Now, the most in-depth genomic analysis of these rare individuals, who account for less than 0.5% of all HIV infections, reveals a clue to their success, which scientists hope will ultimately lead to new strategies to corral the virus in others.

All but one of the 64 “elite controllers” analyzed in the new research have abundant and intact HIV genomes, so-called proviruses, integrated in their cells. But compared with people who have to take ARVs, elite controllers have far more proviruses in chromosome regions where little gene activity occurs, the study finds. Somehow these people have eliminated infected cells with proviruses parked in areas where they more readily co-opt the cellular machinery needed to copy themselves. As a result, elite controllers’ immune systems can handle for prolonged periods—decades in some cases—the low levels of HIV they presumably do produce.

The “comprehensive and elegant study” provides “nature’s proof of principle of how a functional cure [for HIV] is possible,” says Beatrice Hahn, a virologist at the University of Pennsylvania. The challenge now is to identify how to translate this elite controller trick to the far larger HIV-infected population, but the new study “gives us a blueprint,” says Mathias Lichterfeld, an infectious disease physician at Brigham and Women’s Hospital and a co-author of the work, published today in Nature.

When people on ARVs stop the drugs, HIV typically floods their blood within weeks, as “reservoirs” of proviruses in various cells and tissues spring into action. As a result, HIV cure researchers long have attempted to reduce the size of these reservoirs. But the Nature study, led by immunologist Xu Yu of the Ragon Institute of MGH, MIT and Harvard, suggests the size of a reservoir may be less important than limiting proviruses to quiescent chromosome homes.

HIV typically splices its provirus into a cell’s genes, which make up only 1% of the human genome. That helps the virus co-opt the gene transcription machinery needed to churn out new HIVs. But when Yu and colleagues pinpointed the location of nearly 4000 proviruses in cells from the elite controllers and 42 people on ARVs, they found a striking difference. In elite controllers, 45% of the proviruses reside in “gene deserts,” regions of chromosomes where little transcription occurs. In people on ARVs, the number was 17%.

Studies probing how elite controllers manage HIV often are more intriguing than convincing because they rarely include more than a handful from that group. The fact that dozens were examined in the new work impresses Hahn. “Whoever decided to make a concerted effort to compile this cohort is a genius,” she says.

One member of the cohort presents an extreme case: what amounts to a natural cure. The woman, Loreen Willenberg, who was diagnosed as HIV positive in 1992 yet remains healthy without ARVs, had the lowest levels of proviruses of anyone in the study. What’s more, the only proviruses found among the billions of her cells studied were incapable of producing new HIVs. “We did not do integration site analysis on [her] samples, because there’s no intact provirus, and even the defective proviruses were so rare in her genome,” Yu says. (The only other widely accepted HIV cures involve two infected men whose immune systems were destroyed—to treat cancer—and who then received immune cells resistant to the virus.)

Willenberg has a seemingly unharmed immune system despite her untreated HIV infection. She has had her blood levels of HIV monitored for 24 years and has only had one detectable burst of viral replication, when she had a bad bout of the flu. Intensively studied by many HIV scientists, Willenberg nearly 15 years ago established a foundation that helps elite controllers, some of whom joined this clinical study. “If there were some way that this unique state of natural control of HIV infection could be somehow understood and then translated to individuals who did not spontaneously control HIV infection, then that’s what I had to do,” she says.

Previous studies of Willenberg and other elite controllers suggest they frequently have a genetic predisposition to mount stronger immune responses against the virus. Yu and her co-authors suspect this response selectively targeted cells with the most fit proviruses, tilting controllers’ reservoirs toward their hamstrung relatives. A better understanding of this evolutionary immune process might be key to interventions that, in effect, create more elite controllers.

HIV cure studies to date have largely attempted to prod latent proviruses into making new viruses, theoretically setting up those cells for elimination and steadily reducing the size of the reservoir. But this “shock and kill” strategy has had little success, and Lichterfeld would now like to assess cure interventions by quantifying how much they shift the proviral reservoir from gene regions to gene deserts.

Steven Deeks of the University of California, San Francisco, another author on the paper, says the new findings could help the elite controllers. Because of worry that they may suffer chronic inflammation from low levels of HIV replication, many doctors advise this group to still take ARVs. If they have a relatively high level of proviruses in gene deserts, it may be safe for them to stop treatment. “A lot of them now are getting medication they don’t need,” Deeks says.