THE COVID-19 PANDEMIC BROUGHT A VAST MOBILIZATION of scientific ingenuity. At the same time, work on other medical threats continued to push forward. This week, Proto looks at the most transformational non-COVID-19 research of 2020.

Over the past decades, scientists have largely learned how to control HIV infection, which affects 38 million people around the globe. But how to actually cure a person of HIV has remained an elusive holy grail, only documented so far in a tiny handful of cases as the byproduct of a bone marrow transplant. In 2020, researchers moved one tantalizing step closer. A team at the Ragon Institute of MGH, MIT and Harvard documented how HIV can effectively be silenced in the body, and why that mechanism might open the door to a universal treatment.

The insight came from looking at elite controllers—a subset of HIV-positive patients who display a strong natural resistance to the virus. Most patients control the virus through a combination of drugs known as antiretroviral therapy (ART), but HIV remains latent in the genomes of their cells, ready to rebound if that treatment is interrupted. Elite controllers, who make up less than half a percent of the HIV-infected population, also carry HIV in the same genetic reservoirs but don’t require ART and never develop symptoms.

The study, published in Nature, looked at blood samples taken from 64 of these elite controllers who had kept the virus at bay without medication for a median of nine years. New genetic sequencing techniques allowed the team not only to analyze their cells for the number of these viral reservoirs, but also, and for the first time, to precisely map their locations on specific chromosomes. “We wanted to know where the virus is hiding in the human genome and what that tells us about its ability to rebound,” says Xu Yu, a group leader at the Ragon Institute and physician investigator at Massachusetts General Hospital.

The results led to an astonishing new understanding. In elite controllers, HIV is restricted to so-called gene deserts of human DNA where genetic activity is severely curtailed, meaning that they don’t code for many new proteins. In these zones, the virus is unable to replicate and instead remains in a “blocked and locked” state, incapable of causing disease, says Yu. In comparison, for the large majority of people living with HIV, the virus mostly integrates into more active sites within their chromosomes, where it can easily generate new copies of itself and spread throughout the body. When the researchers looked at the blood of other HIV patients on ART, they found significantly fewer viral reservoirs being stored in those inactive regions, meaning that if these patients stop taking their antiviral medication, the virus would begin replicating again.

The immune systems of elite controllers appear to do this genetic quarantining. Though more research is needed to determine how exactly this occurs, the findings point to a new way toward a cure or vaccine, says Yu. “The message to our field is that you don’t need to eliminate or eradicate all of the virus in the human genome in order to achieve a functional cure,” she says, “which removes a major barrier.” Moreover, the findings could lead to more immediate good news for HIV patients. If routine laboratory tests were developed that could determine if viral reservoirs were mostly confined in gene deserts, says Yu, it may be possible to determine if it is safe for some patients to decrease or even be taken off of ART medications, which can have damaging long-term effects.