A study has revealed how an unusual and rare group of people known as “elite controllers” prevent HIV from replicating in their bodies without any need for treatment.
The World Health Organization (WHO) estimate that at the end of 2019 there were 38 million people with HIV infections, globally. To date, the virus has claimed the lives of around 33 million people.
Once inside a host cell, a retrovirus such as HIV replicates by converting its RNA genetic material into DNA and incorporating this into the DNA of the host cell. The virus then hijacks the cell’s RNA and protein-producing machinery to make new copies of itself.
Drugs that prevent HIV from replicating, known as antiretroviral therapy (ART), have proved highly successful at suppressing the virus, allowing many people with HIV to live long, healthy lives.
However, people who take ART still have reservoirs of viable copies of the viral genome in their cells’ DNA. These “proviruses” reactivate as soon as the treatment stops, generating new virus particles.
Meanwhile, scientists have known for some time that around 0.5% of people with HIV somehow suppress the virus without treatment.
Despite having reservoirs of viable HIV incorporated into their cells’ DNA, these individuals — called elite controllers — have undetectable levels of the virus in their bloodstreams.
Finding a treatment that emulates this immune response has been a major goal of HIV researchers, but exactly how elite controllers suppress the virus has remained a mystery.
Now, new research has discovered that elite controllers confine viral DNA to regions of their chromosomes where genes remain inactive, known as gene deserts.
The study, led by scientists from the Ragon Institute, in Cambridge, MA, used next-generation DNA sequencing techniques to compare the chromosomes of 64 elite controllers with those of 41 people receiving ART.
All the participants had HIV-1, the type of the virus that is responsible for the majority of infections worldwide.
The team discovered large numbers of intact viral sequences in the elite controllers’ chromosomes. But in this group, the genetic material was restricted to inactive regions, where DNA is not transcribed into RNA to make proteins.
The study features in a recent issue of the journal Nature.
“This positioning of viral genomes in elite controllers is highly atypical,” says senior author Dr. Xu Yu. “In the vast majority of people living with HIV-1, HIV is located in the active human genes where viruses can be readily produced,” Dr. Yu, also an associate professor of medicine at Harvard Medical School, explains.
The researchers describe this as a “block and lock” mechanism for controlling viruses. The viral DNA is blocked from replicating and effectively locked up inside its host’s DNA.
How elite controllers’ immune systems achieve this effect has yet to be proved, however.
One possibility is that their cells somehow prevent HIV from incorporating its DNA into the active regions of their chromosomes.
But when the researchers grew cultures of elite controllers’ cells in a lab and infected them with HIV, the virus had no trouble integrating its DNA into active regions.
This suggests that, over time, elite controllers’ immune systems may simply eliminate all the infected cells where viral DNA has integrated into active regions and is generating new copies of the virus.
Elite controllers mount a particularly potent immune response to HIV-infected cells. The only cells left may be those in which the virus is blocked and locked, having been randomly integrated into a gene desert.
In an accompanying comment article, Prof. Nicolas Chomont, a microbiologist at the University of Montreal, in Quebec, writes that over time, prolonged attack by the immune system may substantially reduce the reservoir of HIV proviruses in elite controllers:
“This, in turn, suggests that immune-cell therapies […] might not only control viral rebound during ART interruption, but also shrink the viral reservoir to a pool of deeply latent proviruses. Whether this could result in a long-term remission of HIV infection remains, of course, to be determined.”
A treatment that allows people with HIV to stop taking medication is known as a “functional cure” because the people would still have intact HIV in their chromosomes — even if it is locked up in gene deserts.
However, the team discovered that one elite controller in their study had no intact HIV whatsoever in the more than 1.5 billion cells that they analyzed.
This raises the theoretical possibility of a “sterilizing cure,” in which every intact HIV genome has been eliminated. In extremely rare cases, this may occur naturally.