"Cell" identifies the location of HIV's hidden gene

HIV infection is still difficult to cure because the virus is very good at hiding
.
Antiretroviral (ARV) drugs control the infection, but HIV integrates its genes into human chromosomes, evading drugs and the immune system
.
Now, a team of researchers studying some HIV-infected people who have been on treatment for at least nine years has made a tantalizing finding: The longest-lasting integrated HIV genome, or provirus, is increasingly confined to large portions of host DNA.
active fragment, thisPerhaps hinder the production of new viruses, opening up new avenues for therapeutic research
.

In earlier studies, the team found the same "closed" integration in rare HIV-infected people who had not received treatment for decades
.
Together, these findings raise the possibility that HIV and humans can coexist peacefully, says Mathias Lichterfeld, an infectious disease clinician at Brigham and Women's Hospital
.

The group believes that people who have been on treatment for a long time and have been infected with this signature integrated "landscape" could consider stopping treatment to see if their immune systems can check for any residual virus production, which they hope to test in volunteers soon.
a strategy
.

The work was published today in Cell,"Provides a roadmap for a cure for HIV infection," says Steven Deeks, an HIV clinician at the University of California, San Francisco
.
He was not involved in the study, but he did collaborate with Lichterfeld and his colleagues
.

Others are more cautious
.
Mary Kearney, an HIV researcher at the National Cancer Institute, said: "Before treating hundreds [of people with HIV], it's best to be cautious
.
But it's a good start
.
"

For the past 15 years, researchers have tried to clear the reservoir of HIV hidden in the chromosomes of infected people with drugs that stimulate proviruses to produce new viruses
.
White blood cells carrying active proviruses either self-destruct or become easy prey for other immune fighters
.
But these "stimulate and kill" tactics have made little progress
.

The new strategy builds on a landmark study by scientists including Lichterfeld and Xu Yu on "elite controllers," a population of less than 0.
5 percent of untreated HIV Virus-infected people, who have lived with the virus for decades, are not affected significantly
.
In these rare cases, they published a Nature report in 2020, proviruses tend to cluster in chromosomal regions that lack genes, or contain large numbers of inactive genes that encode a protein called zinc fingers (ZNFs) that, intriguingly, evolved to repress retroviruses
.
In both regions, DNA is more compact than other regions in the human genome, making proviruses less accessible to factors that drive transcription
.

Science Translational Medicine on December 15, 2021 ,proposes how these unusual, virus-hostile landscapes evolved among elite controllers
.
Researchers have long thought that potential proviruses could form huge, invisible cellular reservoirs
.
butThis study shows that HIV that integrates into regions of active genes is not completely invisible
.
Instead, infected cells produce small amounts of the new HIV virus, which is eliminated as a result
.

"This reservoir has been described as transcriptionally silent and stable, but we actually found it to be largely transcriptionally active,
" Lichterfeld said.
The team concluded that elite controllers have special immune responses and other obscure mechanisms that accelerate the disappearance of this active reservoir, creating what they call a "skeletal reservoir" controlled by blocked and locked proviruses.
"
.

In the latest study, Lichterfeld and Yu's team examined 1,270 proviruses detected in the blood of six people at different sites during long-term HIV treatment
.
In three of them, the team found that the complete HIV gene gradually accumulated in the human gene desert and the quiescent ZNF gene
.
"It's a bit like a chess game: there's only a few places left for the king," Lichterfeld said
.
The result: an integrated environment that increasingly resembles an elite controller
.

Some scientists believe that why viral DNA persists in these genes is a mystery for further study;This could be an accident, or it could be a role played by the action of the ZNF protein
.

The key to the new study is to show that HIV treatments, not just the unusual immunity of elite controllers, can bring the virus into these quiescent regions
.
"People don't necessarily have to be elite and special, but, instead, we might be able to induce the same phenotype in other people
.
"

How to do this is still an open question
.
Researchers have proposed several ideas to speed up the blocking and locking process, including the use of drugs that target proviral genes, disrupt transcription machinery or therapeutic vaccines to speed up the clearance of transcribed proviruses
.
Others hope that long-term treatment with standard antiretroviral drugs will suffice
.

Yu and Lichterfeld said participants in one of their studies, a man who had been on antiretroviral therapy for more than 20 years and had a reservoir landscape resembling an elite controller, had agreed to stop treatment to test their hypothesis
.
Last month, at a conference in Boston on how to control HIV without antiretroviral drugs, 24 attendees decided to seek funding for a new collaboration, led by Yu
.
It hopes to recruit large numbers of people who have been on antiretroviral drugs for decades to study their HIV integration and find more candidates for treatment-disruption studies
.

Dawn Averitt recently participated in a pilot study that had Yu and Lichterfeld examine her for the provirus
.
She said she was concerned that the drug had suppressed her virus for more than 20 years, even though the analysis indicated she was a good candidate to stop treatment
.
"It was really nerve-wracking," Averitt said.
The devil you know is always better than the devil you don't, right? "

Still, Averitt said, if invited, she might participate in the study, mostly to help others
.
"I know how to use these drugs, but I really care what it means for all of us," she said
.
Imagine what it means to be able to say 'Worry about getting it under control now, not worrying forever'
.
"

   Original text retrieval: Parallel analysis of transcription, integration, and sequence of single HIV-1 proviruses