Findings could lead to the development of an approach allowing for a safe, lifelong immunity to HIV.
Scott Kitchen, PhD
New study findings report that the first US Food and Drug Administration (FDA)-approved gene therapy for cancer, demonstrated the potential to suppress and eradicate HIV in lab animals.
The small study, published in PLOS Pathogens, tested genetically engineered chimeric antigen receptor (CAR) cells on 2 macaque monkeys and cells in growing lab dishes. This suggests that scientists can genetically modify the immune system to better fight HIV, potentially leading to the development of an approach for safe, lifelong immunity.
"I believe that the important aspect of our study is that it shows that blood-forming stem cells can be treated to produce mature T cells that target HIV for the long-term, potentially providing lifelong immunity," Scott Kitchen, PhD, director, UCLA CFAR/JCCC, David Geffen School of Medicine, told MD Magazine. "A proper immune response would be critical in eradicating HIV from the body, and we are attempting to fix a critical component of the immune system to allow this to occur. This lays the foundation for future work in developing approaches to engineer the immune system to better target HIV or other infections or malignancies.”
The experiment involved genetically modifying stem cells that produce immune-system T cells and other blood cells. This gave the hematopoietic stem cells an HIV-specific CAR receptor. One part, CD4, hunts down and binds the AIDS-causing virus, while another, C46, interferes with the infection’s ability to enter a T cell.
The genetic modifications protected the T cells from being infected with the disease themselves, and allowed them to find and destroy HIV-infected cells, some of which have the same T-cell-attracting surface molecules as HIV.
With these modifications, the CAR-T cells act as sentinels and offer a robust response to the virus in infected cells. This study was the first time such a method yielded results in a relevant large-animal model.
The engineered cells not only destroyed infected cells but showed efficacy in attacking and killing the HIV-infected cells in both the petri dishes and macaque monkeys, and also persisted for more than 2 years without any adverse effects — suggesting the potential to create long-term immunity from the virus.
While CAR-T has shown promise in treating HIV prior, this new approach found that the primate’s bodies kept producing the CAR-expressing cells for more than 2 years after the initial infusion without reactions.
The cells were widely distributed throughout the lymphoid tissues and gastrointestinal tract, major anatomic sites for HIV replication and persistence in those with HIV. Creating CAR stem cells could produce an endless supply of engineered T cells that continue to attack HIV and bind to sites where HIV tends to replicate and persist at the highest rates.
Researchers noted that the technique did not eradicate infected cells in which the virus was dormant, and therefore future studies should focus on a combination approach with other treatment strategies like antiretroviral therapy (ART), which could raise the possibility that CAR-Ts may eradicate HIV from where it hides in the body.
This study suggests a long-term solution where the stem cell approach has greater potential to suppress HIV long term, attack dormant HIV, reduce a person’s dependence on antiviral medications and even eradicate HIV from the body.
Human trials of the treatment technique could begin within the next 2—3 years, as researchers have been in communication with a private gene therapy company Calimmune, and others, to develop an approach.
Barriers stand between preliminary results and a real-world treatment. Price is the main issue, since initially engineered stem cells would be an expensive approach but could save the necessity and expense of being on ART. Researchers are working on developing the engineered cells as a vaccine, to perhaps make it more affordable.