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An HIV infection remains maddeningly difficult to cure because the virus is so good at hiding out. Yes, antiretroviral (ARV) drugs can control an infection, but HIV integrates its genes into human chromosomes, evading both drugs and the immune system. Now, a research group studying a handful of HIV-infected people who have been on treatment for at least 9 years has made a tantalizing discovery: The integrated HIV genomes, or proviruses, that persist the longest are increasingly confined to largely inactive stretches of host DNA, perhaps stymieing production of new viruses—and opening new avenues for cure research.

In earlier work the team had found the same “blocked and locked” integration phenomenon in rare HIV-infected individuals who remain healthy for decades without treatment. Together, the findings raise the possibility of “a peaceful coexistence between HIV and humans,” proposes Mathias Lichterfeld, an infectious disease clinician at Brigham and Women’s Hospital who led the new analysis.

The group believes long-treated, infected people with this signature integration “landscape” could consider stopping treatment to see whether their immune systems can check any remaining virus production, a strategy they hope to test in a volunteer soon.

The work, published today in Cell, “provides a road map to a cure” for HIV infections, says Steven Deeks, an HIV clinician at the University of California, San Francisco, who was not part of the study but has collaborated with Lichterfeld and his colleagues. Others are more circumspect. “It’s good to be cautious until this is done on hundreds of [HIV-infected people],” says Mary Kearney, an HIV researcher at the National Cancer Institute. “But this is a great start.”

Over the past 15 years, researchers have tried to drain the reservoirs of HIV hiding in the chromosomes of infected people with drugs meant to prod the proviruses into producing new viruses. The white blood cells that harbor the active proviruses then either self-destruct or become easy prey for other immune warriors. But these “shock-and-kill” strategies have made little headway.

The new strategy builds on a landmark study in which Lichterfeld, Xu Yu of the Ragon Institute of MGH, MIT and Harvard, and other scientists examined “elite controllers,” the tiny group of untreated HIV-infected people—less than 0.5%—who live with the virus for decades and suffer no obvious harm from it. In these rare cases, they reported in 2020 in Nature, the proviruses tended to cluster in regions of chromosomes that lack genes or harbor largely inactive genes that code for a type of protein known as a zinc finger (ZNF)—which, intriguingly, evolved to repress ancient retroviruses. In both kinds of regions, the DNA is more tightly packed than elsewhere in the human genome, making proviruses less accessible to factors that drive transcription.

In the 15 December 2021 issue of Science Translational Medicine (STM), Yu and Lichterfeld—who are married—followed up on that finding by proposing how these unusual, virus-hostile landscapes might evolve in elite controllers. (Deeks was a co-author.) Researchers have long thought latent proviruses can form large, effectively invisible cellular reservoirs. But the STM study suggests HIV integrated into regions with active genes is never entirely invisible. Instead infected cells produce a trickle of new HIV and, as a result, get eliminated.

“The reservoir has always been described as transcriptionally silent and stable, but we actually find it’s transcriptionally active to a large extent,” Lichterfeld says. The team concluded that elite controllers have special immune responses and other murky mechanisms that speed the elimination of this active reservoir, resulting in what they described as a “skeleton reservoir” dominated by blocked and locked proviruses.

Dawn Averitt
Dawn Averitt has been on antiretrovirals for many years to control her HIV infection and says the idea of stopping treatment to test a cure strategy is “nerve wracking.” Stephanie Gross

In the latest work, Lichterfeld’s and Yu’s team examined 1270 proviruses detected in the blood of six people at different points during prolonged HIV treatment. The group found that in three of the people, intact HIV genes gradually accumulated in human gene deserts and the quiescent ZNF genes. “It’s a little bit like a chess game: There are only a few spots left where the king can still go,” Lichterfeld says. The result: an integration landscape increasingly similar to the one seen in the elite controllers.

Independently, Lillian Cohn, an immunologist at the Fred Hutchinson Cancer Research Center, made a similar finding: In people on ARVs for between 4 and 21 years, HIV proviruses were preferentially integrated in certain ZNF genes. Why viral DNA persists in those genes is a mystery that demands further study, some scientists suggest; it may be an accident, or the actions of the ZNF proteins may play a role.

What’s key in the new study, Cohn notes, is showing that HIV treatment, and not just the unusual immune abilities of elite controllers, can drive the virus into those quiescent regions. “It doesn’t necessarily need to be that people are somehow elite and special, but, rather, we might be able to induce this same phenotype in other people,” she says.

How to do that remains an open question, Cohn notes. Researchers have floated several ideas for accelerating the block-and-lock process, including using drugs that target the proviral genes and gum up transcription machinery or therapeutic vaccines that speed elimination of the transcribing proviruses. Others hope that long-term treatment with standard ARVs will be enough.

Yu and Lichterfeld say a participant in one of their studies, a person treated with ARVs for more than 2 decades who has a reservoir landscape resembling an elite controller, has agreed to stop treatment to test their hypothesis. And last month at a meeting in Boston on how to control HIV without ARVs held by amfAR, a foundation that supports HIV/AIDS research, the two dozen attendees decided to seek funding for a new collaboration, headed by Yu. It hopes to enroll large numbers of people who have been on ARVs for decades to examine their HIV integration landscapes and find more candidates for treatment interruption studies.

Dawn Averitt, who recently joined a pilot study to have her proviruses examined by Yu and Lichterfeld, says even if the analysis suggests she is a good candidate to stop treatment, she’s scared—the drugs have suppressed her virus for more than 20 years. “It’s nerve wracking,” says Averitt, who started a nonprofit, the Well Project, to help women living with the virus and later founded the Women’s Research Initiative on HIV/AIDS. “The devil you know is better than the devil you don’t, right?”

Still, Averitt says if invited, she’d probably join the study, primarily to help others. “I figured out how to do the dance with these drugs, but I really care what it means for all of us,” she says. “Imagine the hope, imagine the possibility, of being able to say, ‘Worry about keeping it under control now, don’t worry about what this means forever.’”

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