Can gene-editing cure HIV? New study eliminates virus in mice

Dr. Kamel Khalili poses with Temple University HIV researchers. (Temple University)

Could gene-editing be the long sought after answer for how to effectively eliminate HIV?

The possibility is growing stronger, according to researchers who have successfully combined gene-editing with antiretroviral drugs to cure animals of HIV — a feat they have now pulled off more than once.

The study, published in the peer-reviewed journal The Proceedings of the National Academy of Sciences (PNAS) this week, describes how researchers modified a previous gene-editing strategy to aim at two specific targets — HIV-1, the virus which causes AIDS, and the co-receptor which allows the virus to enter cells, called CCR5.

Their success in eliminating HIV within mice underlines how important CCR5 is in isolating a cure and bringing that to humans, researchers say.

HIV is a deadly virus which attacks the body’s immune system. Without treatment, it can lead to AIDS, the more advanced form of the disease. More than 40.1 million people have died of HIV, according to the World Health Organization.

While an HIV diagnosis used to be a death sentence, the advent of antiretroviral drugs as treatment has allowed those with HIV to live their lives without the disease progressing and without the fear of passing it on to others.

However, scientists are still searching for an actual cure.

“Curing HIV is the big picture,” Howard E. Gendelman, professor and chair of the Department of Pharmacology and Experiential Neuroscience at the University of Nebraska Medical Center (UNMC), said in a press release. “Through our ongoing collaboration, Temple and UNMC have carried out meaningful research that could ultimately impact the lives of many people.”

Gendelman is one of the authors behind this new research. For years, he has been partnering with a team led by Kamel Khalili, professor and director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine at the Temple University, combining their individual HIV research to better pursue an HIV cure.

This new study is the latest step in their work together.

Gendelman’s team is behind the development of a technique called LASER-ART, which stands for “long-acting slow-effective release antiretroviral therapy” which allows for the frequency of antiretroviral therapies to combat HIV to be decreased. Khalili’s team focuses on CRISPR gene-editing technology.

CRISPR gene-editing works by precisely cutting DNA strands and then allowing the natural DNA processes to take over to repair the break. This strategy means that specific sections of the DNA can be removed, added or altered with a high specificity, which is important when you’re handling very complex building blocks of living organisms.

Previously, the two teams had established that by combining LASER-ART with CRISPR gene-editing technology, HIV could be edited out of the genomes of live, humanized HIV-infected mice. When a lab animal is “humanized” it means it has been engrafted with a small part of human DNA or tissue, such as a tumour, in order to better research treatments and interventions for human problems within animal models prior to human clinical trials.

During this previous study, first revealed in 2019, researchers were able to cure some of the mice. However, the fact that only a few of the mice recovered meant researchers didn’t know if it was a fluke or not.

Another issue—despite being able to eliminate HIV in the tissue of the mice, researchers found it could still reemerge, similar to how humans who have been receiving antiretroviral therapy regularly but then stop treatment will experience a rebound infection.

In order to figure out how to stop rebound infections, researchers turned to the few isolated cases of HIV being eliminated in humans.

That’s when the new focus on the receptor CCR5 came into the gameplan.

“The idea to bring together the excision of HIV-1 DNA with inactivation of CCR5 using gene-editing technology builds on observations from reported cures in human HIV patients,” Khalili said.

“In the few instances of HIV cures in humans, the patients underwent bone marrow transplantation for leukemia, and the donor cells that were used carried inactivating CCR5 mutations.”

Researchers decided to modify the CRISPR technology in combination with LASER ART to target two things at once — the virus and the receptor — in the hopes of removing the virus permanently.

“Our hypothesis was that the loss of the virus’s receptor, CCR5, is important to permanently eliminating HIV infection,” Khalili explained in the release.

They found that using this strategy, they were able suppress the virus, restore human T-cells and eliminate replicating HIV-1 in more than half of the mice.

This is a much bigger percentage of the mice sample compared to their earlier attempts at eliminating HIV in mice. These findings, researchers say, strongly support the theory that CCR5 is a key area to target in eliminating HIV.

“We are true partners, and what we achieved here is really spectacular,” Gendelman said in the release. “Dr. Khalili’s team generated the essential gene-editing constructs, and we then applied those constructs in our LASER-ART mouse model at Nebraska, figuring out when to administer gene-editing therapy and carrying out analyses to maximize HIV-1 excision, CCR5 inactivation, and suppression of viral growth.”

They believe that this dual CRISPR gene-editing strategy, which focuses on those two targets at the same time, could be hugely successful in humans when refined.

And considering the few human cures that have been seen before required an intensive treatment reserved for leukemia, this would be far more accessible.

“It is a simple and relatively inexpensive approach,” Khalili said. “The type of bone marrow transplant that has brought about cures in humans is reserved for patients who also have leukemia. It requires multiple rounds of radiation and is not applicable in resource-limited regions, where HIV infection tends to be most common.”

The next step for researchers will be testing the dual gene-editing strategy in non-human primates — and if that goes well, human trials could be on the horizon.