Identification of Viral Reservoirs Could Lead to a Functional Cure for HIV

In the more than 35 million people worldwide with HIV, the virus can be controlled with a daily regimen of antiretroviral drugs (ART), but not cured. According to results from a recent study, a functional cure may lie in identifying the viral reservoirs in which HIV places copies of its viral genetic material into cell genomes.

In most patients with HIV, these viral reservoirs in cell genomes exist as sanctuaries for HIV to replicate throughout the body, despite treatment with ART. For people with HIV, this means that treatment with ART is necessary to keep the virus from replicating and causing a rapid viral rebound and disease progression.

However, there are some people with HIV who suppress the virus naturally without the need for medication, which researchers refer to as elite controllers. In these individuals, their immune systems use a T-cell mediated immune response that is able to control the virus without support from medication.

In order to assess the difference in the viral reservoirs of elite controllers from other patients with HIV, the researchers used next-generation sequencing techniques to map the locations of the intact HIV genomes within the human genomes.

The researchers observed that in elite controllers, HIV was often present in inactive parts of the genome that the researchers called gene deserts. These areas have human DNA that is never turned on, causing HIV to not be able to express itself effectively. This then causes the virus to stay locked in the cell genome, blocking it from being able to replicate in the body.

"This positioning of viral genomes in elite controllers 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," said study co-author Xu Yu, MD, an associate professor of medicine at Harvard Medical School, a physician investigator at Massachusetts General Hospital, and an associate immunologist at Brigham and Women’s Hospital, in a press release.

In order to assess the role of the gene deserts further in the suppression of the virus, the researchers collected cells from the elite controllers and tested them further in the lab. By infecting them with HIV in that setting, the researchers found the virus integrated into the active sites in the cell genomes, but not in the inactive gene deserts. This finding suggested to the researchers that the source of the virus suppression was the elite controllers’ T cell response, which eliminated intact viral genomes from active sites.

Based on these findings, the researchers posited that if they could identify the viral reservoirs where the virus replicates after treatment with ART stops, it may be possible to develop a treatment against the active, or rebound-competent, reservoirs.

Specifically, if the researchers are able to activate the type of T cell immunity exhibited in elite controllers, the elimination of rebound-competent reservoirs could be possible, halting the replication of the virus. Any remaining viral DNA would act similarly as it does in elite controllers, as the virus in their bodies remains blocked from further replication. This could achieve a functional cure for patients with HIV.

Additionally, the researchers observed 1 elite controller in particular who had no intact HIV in more than 1.5 billion cells that were analyzed. The researchers questioned whether this demonstrates that a cure in which an individual’s immune system has removed all intact HIV genomes from the body could also be possible in some rare cases, resulting in what they referred to as a sterilizing cure.

REFERENCE

Unique HIV reservoirs in elite controllers. Boston, MA: Massachusetts General Hospital; August 26, 2020. sciencedaily.com/releases/2020/08/200826110326.htm. Accessed September 2, 2020.