Some rare people may essentially be able to cure themselves of HIV infections.
Twice, people infected with HIV have had levels of the virus in their bodies drop to undetectable levels after bone marrow transplants, never to return (SN: 3/5/19). Now it appears that a person may have cleared functional HIV with no outside help. If true, it would be the first known instance of a spontaneous cure.
Analysis of more than 1.5 billion cells taken from a patient known as EC2 showed no functional HIV copies in any of them, researchers report August 26 in Nature. The person still had some nonfunctional copies of the virus. While no one can say for sure that intact virus isn’t hiding in a cell somewhere in this person’s body, the finding suggests that some people’s immune systems can get the upper hand, essentially eliminating the pernicious and persistent virus.
A second person, EC1, had just one functional copy of HIV in more than 1 billion blood cells analyzed. And that copy of HIV was stuck in what is essentially a genetic supermax prison. That genetic lockup may be key to being able to naturally control the virus.
Those two people are part of a rare group of people known as elite controllers, meaning they are able to maintain very low or undetectable levels of HIV without antiretroviral drugs. These people have no symptoms or clear signs of damage from the virus. “It’s not even that we’re talking about a few months or a few years. It’s extremely long-term,” says Satya Dandekar, an HIV researcher at the University of California, Davis School of Medicine who was not involved in the study. In contrast, for 99.5 percent or more of the world’s 35 million people infected with the virus, drugs are the only way to keep the virus down.
Researchers want to know how elite controllers quash the virus for long periods of time. It has been difficult to figure it out, Dandekar says, because no one has recorded the first fight scenes between HIV and the elite controllers’ immune systems. “We miss the initial punches the immune system has thrown at the virus.” And by the time anyone recognizes an elite controller, the fight is already won.
About a quarter of elite controllers have genetic variants in key immune system genes that may help them get a handle on the virus, says Joseph Wong, a virologist at the University of California, San Francisco. But that explains what’s going on in only a minority of elite controllers, and isn’t something easily transferred to others, he says.
It’s possible that the elite controllers were infected with “wimpy” versions of HIV, Dandekar says. So the researchers examined the HIV viruses embedded in DNA from 64 elite controllers and 41 HIV-infected people taking antiretroviral drugs. The elite controllers had maintained undetectable levels of virus without drugs from one to, in EC2’s case, 24 years. The median was nine years.
HIV is a retrovirus, which means that it stores its genetic information as RNA. An enzyme called reverse transcriptase copies those RNA instructions into DNA, which can then insert into the host’s DNA. Reverse transcriptase is error prone, often resulting in defective or incomplete copies of the virus. So the researchers went into the study thinking that elite controllers might be loaded with these nonfunctional versions, which can’t make infectious virus, says Xu Yu, an immunologist at the Ragon Institute of MGH, MIT and Harvard in Boston.
“But to our surprise, that’s not the case,” she says. Instead, most elite controllers in the study have more intact virus than expected. So Yu and colleagues looked to see where the virus had landed in patients’ DNA.
In most people infected with HIV, the virus lands near or in genes, thanks to some human proteins that shepherd it there, says Monica Roth, a virologist at Rutgers University Robert Wood Johnson Medical School in Piscataway, N.J. But in the elite controllers, the virus was trapped in gene-poor parts of the human genetic instruction book, or genome. When it did land in or near genes, they were ones that are wrapped in the molecular equivalent of razor wire, which prevents the genes from being turned on. Collectively those inactive, tightly guarded parts of the genome are known as heterochromatin.
Plunking HIV in heterochromatin “is like putting it in the trunk, and then locking the trunk,” says Roth, who was not involved in the work. Those silenced copies of HIV might briefly stir and produce infectious virus, but would mostly be inert.
Yu and colleagues investigated whether elite controllers have a propensity for steering the virus to heterochromatin. But in lab dishes, the guide proteins in elite controllers’ cells still direct HIV insertions in or near genes, just like what happens in the cells of other people.
“It’s probably not that [elite controllers] just got lucky at the beginning of the infection” to get HIV trapped in heterochromatin, says Yu’s Ragon Institute colleague, Mathias Lichterfeld, a virologist and infectious diseases physician. Instead, the researchers think elite controllers’ immune systems eliminated cells producing functional virus, leaving behind only broken copies of the virus and intact versions locked in heterochromatin. Exactly how the immune system manages that feat isn’t known.
“It’s very intriguing that they’re proposing this,” Roth says. “But there’s no evidence saying that it happens.” Even so, she says, the study may hold hope for others infected with HIV.
“Once you figure out the mechanism [by which] this is working, maybe you can figure what goes wrong in everyone else and fine-tune it,” Roth says. The researchers have eliminated some possibilities, but haven’t solved the mystery yet of how elite controllers achieve their status. “The big question is, how do you do it? It’s a cliffhanger in the paper.”