By Marie Rosenthal, MS
The immune system of elite controllers—people living with HIV who suppress the virus without antiretroviral therapy (ART)—use a T-cell–mediated immune response that holds the virus in a “gene desert,” where it cannot be used to replicate.
New research provides an in-depth look at how this response works in elite controllers (Nature 2020;585:261-267). Using next-generation sequencing techniques, researchers from the Ragon Institute of MGH, MIT and Harvard sequenced billions of cells from 64 elite controllers and 41 HIV-positive people taking ART.
They were able to map precisely the locations of intact HIV genomes in the human genome.
Xu Yu, MD, the Ragon group leader, and his colleagues found that in elite controllers, HIV was often found in locations of the genome that researchers call gene deserts. In these inactive parts of the human genome, human DNA is never turned on, and HIV cannot be effectively expressed. Instead, it is “blocked and locked” in the cell’s genome, unable to replicate, and therefore, incapable of causing disease.
“This positioning of viral genomes in elite controllers,” Dr. Yu said, “is highly atypical, as in the vast majority of people living with HIV-1, HIV is located in the active human genes where viruses can be readily produced.” (Fewer than 1% of people with HIV are thought to be elite controllers.)
When the researchers collected cells from elite controllers and infected them with HIV in the lab, they found the virus integrated into active sites in the cell genomes, not in the inactive gene deserts, just as they do in most people with HIV. This suggests that the elite controllers’ unique viral reservoirs may be a result of their HIV-suppressing T-cell response eliminating intact viral genomes from active sites.
Upon infection, retroviruses like HIV place copies of their viral genetic material into the cells’ genomes, creating viral reservoirs throughout the body. There, the HIV takes sanctuary and persists despite ART. For people living with HIV, this means that if they stop taking ART, the intact viral genomes integrated into the cells’ genomes start replicating, leading to rapid viral rebound and disease progression.
This HIV viral reservoir has remained a major obstacle to curing HIV.
“We knew that HIV elite controllers have a robust HIV-specific T-cell immune response and a relatively small HIV reservoir. What this paper adds is an in-depth characterization of the HIV reservoir in elite controllers, including the frequency of intact proviruses and where they are integrated into the host genome,” explained Jonathan Z. Li, MD, an assistant professor at Harvard Medical School, in Boston, who has been working with elite controllers for several years.
Dr. Li highlighted several novel findings from the report that demonstrate how the HIV reservoir of elite controllers differs from that of ART-treated individuals:
- The size of the reservoir is smaller in elite controllers, but the frequency of intact proviruses is actually higher than ART-treated individuals.
- The number of human leukocyte antigen escape mutations was lower, suggesting that these reservoirs were seeded relatively early on.
- The host chromosomal integration sites of the proviruses appeared to have distinct features seen in the elite controllers, suggesting that their proviruses are more likely to be in a state of deeper latency.
- Because CD4 cells from elite controllers can be infected in vitro, these unusual integration sites are not due to an intrinsic property of the host cells, but are likely mediated by an effective host immune response that has cleared cells with more active proviruses.
Understanding the interplay between their immune system and HIV may hold the key to helping other people living with HIV to suppress the virus without daily treatment, achieving what is known as a functional cure, according to Dr. Yu.
Dr. Yu’s group had one more finding: One of their elite controller participants had no intact HIV found in over 1.5 billion cells analyzed. This raises the possibility that a “sterilizing cure” of HIV, in which the participant’s immune system has removed all intact HIV genomes from the body, may be achieved naturally in extremely rare instances.
“This report details one individual who has been followed for more than 24 years without significant viral rebound. Despite sampling a huge amount of cells in the peripheral blood and gut, the authors were unable to detect any intact provirus,” Dr. Li said. “While a subset of elite controllers may eventually lose viral control, these results are reminiscent of the reservoir studies for the Berlin and London patients. Only time will tell whether this is a case of an HIV cure.”
Elite controllers still should be followed by their physician, and follow-up should include regular viral load and CD4 testing, according to Dr. Li, because a subset of elite controllers see a loss of CD4 cells over time and lose control of the virus.
“For HIV controllers who have detectable virus in the blood, recent studies have shown that ART can further suppress signs of inflammation. Whether ART is needed in elite controllers who are able to keep their virus completely suppressed is still unclear,” he said.
“This report shows that there’s still a lot that we don’t know about HIV elite controllers and how to translate the mechanisms of control to a treatment for everyone else,” Dr. Li said.
“Unfortunately, long-term ART does not appear to be able to replicate the reservoir characteristics seen in ECs [elite controllers], but understanding the mechanisms behind how rare individuals are able to keep HIV suppressed without ART moves us one step closer to finding strategies to induce HIV remission,” added Dr. Li, who sits on the editorial advisory board of Infectious Disease Special Edition.
This project was supported by the National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institutes of Health; Mark and Lisa Schwartz Family Foundation; Ragon Institute of MGH, MIT and Harvard; Bill & Melinda Gates Foundation; and Foundation for AIDS Research (amfAR).
