Global Courant 2023-05-04 07:13:00
Could gene editing be the long-sought answer to effectively eliminating 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’ve now accomplished more than once.
The study, published in the peer-reviewed journal The Proceedings of the National Academy of Sciences (PNAS) describes this week how researchers modified a previous gene-editing strategy to target two specific targets: HIV-1, the virus that causes AIDS, and the co-receptor that allows the virus to enter cells, called CCR5.
Their success in eliminating HIV in mice underscores the importance of CCR5 in isolating a drug and bringing it to humans, researchers say.
HIV is a deadly virus that attacks the body’s immune system. Without treatment, it can lead to AIDS, the more advanced form of the disease. According to the World Health Organization, more than 40.1 million people have died from HIV.
While an HIV diagnosis used to be a death sentence, the advent of antiretroviral drugs as a treatment has enabled people living with HIV to live their lives without the disease getting worse and without the fear of passing it on to others.
However, scientists are still looking 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 continued collaboration, Temple and UNMC have conducted meaningful research that could ultimately impact the lives of many people.”
Gendelman is one of the authors behind this new study. He has been working for years with a team led by Kamel Khalili, professor and director of the Comprehensive NeuroAIDS Center at Temple University’s Lewis Katz School of Medicine, combining their individual HIV research to achieve better HIV cures. pursue.
This new study is the latest step in their collaboration.
Gendelman’s team is behind the development of a technique called LASER-ART, which stands for “long-acting slow-effective release antiretroviral therapy,” that could reduce the frequency of antiretroviral therapies used to fight HIV. Khalili’s team focuses on CRISPR gene editing technology.
CRISPR gene editing works by precisely cutting DNA strands and then letting natural DNA processes take over to repair the break. This strategy means that specific parts of the DNA can be removed, added or changed with high specificity, which is important when working with highly complex building blocks of living organisms.
Previously, the two teams had determined that by combining LASER-ART with CRISPR gene-editing technology, HIV could be removed from the genome of live, humanized HIV-infected mice. When a test animal is “humanized,” it means that it has been grafted with a small portion of human DNA or human tissue, such as a tumor, to better research treatments and interventions for human problems in animal models prior to human clinical trials.
In this previous study, first revealed in 2019, researchers were able to cure a few mice. However, the fact that only a few of the mice recovered meant that researchers didn’t know if it was a fluke or not.
Another problem: Despite being able to eliminate HIV in the mice’s tissues, the researchers found that it could still resurface, similar to how people who have been on regular antiretroviral therapy but then stop treatment, will experience a rebound infection.
To figure out how to stop rebound infections, researchers turned to the few isolated cases where HIV was eliminated in humans.
Then the new focus on the receptor CCR5 entered the game plan.
“The idea of conflating the excision of HIV-1 DNA with the inactivation of CCR5 using gene editing technology builds on observations of reported cures in human HIV patients,” Khalili said.
“In the few cases of HIV cure in humans, the patients underwent bone marrow transplantation for leukemia, and the donor cells 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 hopes of permanently removing the virus.
“We hypothesized that the loss of the virus’s receptor, CCR5, is important for permanently eliminating HIV infection,” Khalili explains in the release.
They found that with this strategy they were able to suppress the virus, restore human T cells and eliminate HIV-1 replication in more than half of the mice.
This is a much larger percentage of the mouse sample compared to their previous attempts to eliminate 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 have achieved here is truly spectacular,” said Gendelman in the release. “Dr. Khalili’s team generated the essential constructs for gene editing, and we then applied those constructs in our LASER-ART mouse model in Nebraska to figure out when to administer a gene-editing therapy and perform analysis. to HIV-1 excision, CCR5 inactivation and suppression of viral growth.”
They believe this dual CRISPR gene-editing strategy, which simultaneously targets those two targets, could be hugely successful in humans if refined.
And since the few human cures seen before required intensive treatment reserved for leukemia, this would be much more accessible.
“It’s a simple and relatively inexpensive approach,” Khalili said. “The type of bone marrow transplant that has brought healing to 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 is most common.”
The next step for researchers is to test the dual gene-editing strategy in non-human primates — and if that goes well, human trials could be in the offing.
