The rise in the development of chimeric antigen receptor (CAR) T cells for use against various forms of cancer has been well documented due to encouraging results in recent years. Yet, the earliest CAR T-cell trials were done in the early 1990s for HIV-1 infections but were sidelined due to less than efficacious results. However, many scientists believe that the emerging number of broadly neutralizing antibodies (bnAbs) could provide real opportunities to reconsider CAR T cells as a viable approach for HIV immunotherapy.
Now, investigators from the UCLA AIDS Institute and Center for AIDS Research have reported on their recent results surrounding the discovery of potent antibodies that can be used to generate CAR T cells that kill HIV-1–infected cells.
CARs are genetically engineered immune T cells that produce receptors on their surface designed to target and kill specific cells containing viruses or tumor proteins. Chimeric receptors are the focus of ongoing research into how gene immunotherapy can be used to fight cancer. However, they could also be used to create a strong immune response against HIV.
Interestingly, the human immune system does initially respond to and attack HIV, although it quickly becomes overwhelmed due to the rapid viral replication and ability to sequester itself within immune cells to avoid further elimination—destroying the immune system and leaving the body vulnerable to a host of infections and diseases. Over the years researchers have been looking for ways to strengthen the immune system against HIV, and it now appears CARs could be a viable weapon in that fight.
“We took new generation antibodies and engineered them as artificial T-cell receptors, to reprogram killer T cells to kill HIV-infected cells,” explained senior study author Otto Yang, M.D., professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA and director of vaccine and pathogenesis research at the AIDS Institute and Center for AIDS Research. “what works in a test tube doesn't necessarily work in a person, so the next step is to find strategies to put these receptors into humans. But this therapy shows enough promise to move forward with further research.”
The findings from this study were published recently in the Journal of Virology in an article entitled “HIV-1-Specific Chimeric Antigen Receptors Based on Broadly-Neutralizing Antibodies.”
The UCLA team utilized seven recently discovered bnAbs that have the ability to bind multiple strains of invading viruses, unlike earlier isolated antibodies that tend to bind few strains. These antibodies were re-engineered as artificial CAR T-cell receptors to have activity against broad strains of HIV.
“We used sequences from seven well-defined bnAbs varying in binding sites and generated single chain-antibody-based CARs,” the authors wrote. “These included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity (reduction of viral replication in log10 units) to transduced CD8+ T lymphocytes.”
While the receptor approach has been in use for almost 10 years to fight cancer, this is the first attempt in 15 years to use the technique to treat HIV, when initial studies proved ineffective.
The researchers were excited by their findings stating that the “antiviral activity [of these CARs] was reproducible but varied according to the strain of virus. These findings indicated that bnAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1.”
However, Dr. Yang did urge caution in over-interpretation of the results, noting that “what works in a test tube doesn't necessarily work in a person, so the next step is to find strategies to put these receptors into humans. But this therapy shows enough promise to move forward with further research.”