Second generation CAR against HIV
Due to the resistance of HIV reservoir cells, combined antiretroviral therapy (ART) is insufficient to eliminate the virus. Chimeric antigenic receptors (CAR) of T cells are a powerful tool of immunotherapy, demonstrating promise in the treatment of HIV infection. A research team from the University of California at Los Angeles has shown in mouse models that the use of a truncated form of the CD4 molecule for HIV immunotherapy gives a high and stable result, surpassing similar methods of treatment using CD4.
CAR T-cell therapy consists in the genetic modification of the body's own cells to create HIV-fighting T-lymphocytes. With this approach, the preservation, development and maintenance of T-cell function remains the main problem. The group has previously demonstrated successful production of anti-HIV CAR-T cells from modified hematopoietic stem cells (HSCs) in vivo. As soon as these genetically engineered HSCs enter the body, they form specialized infection-fighting lymphocytes – CAR T cells that find and kill cells infected with HIV.
Researchers have shown that T-lymphocyte-based therapy has the potential not only to destroy infected cells, but also to create memory cells that can provide lifelong protection against infection with the virus that causes AIDS a few months or years after therapy.
In a new study, the team reported the development and successful testing of a second-generation CD4-based in vivo CAR (CD4CAR) against HIV infection using a HSC-based approach. Since HIV binds to CD4 molecules to infect cells, the researchers created a CAR molecule containing a CD4 fragment.
When the virus interacts with CD4 CAR T cells, other CAR sites activate the cell, which eventually destroys the virus. But CAR, in addition to CD4, contains two more domains that can allow HIV infection.
The researchers removed these domains, adding another one that makes cells resistant to infection and provides a more effective and long-lasting cellular response against HIV than before. Although the previous approach allowed for the continuous production of new HIV-fighting T cells that persisted for more than two years, these cells were essentially inactivated until HIV entered the body. A new modified CD4-based truncated CAR with a 4-1BB domain (D1D2CAR 4-1BB) forms the body's immune response to HIV, rather than waiting for the virus or parts of the virus to trigger a response, almost in the same way that vaccines force the immune system to respond to the virus. The new approach also leads to the production of a significant number of memory T cells that are able to respond more efficiently and quickly to reactivated HIV.
Mice with D1D2CAR 4-1BB showed faster viral suppression in combination with ART and better persistence of CAR T cells during ART.
The data obtained give an idea of the types of CAR molecules and tactics that are suitable for immunotherapy using hematopoietic stem cells and that ensure optimal function and stability of CAR T cells after development from HSC.
Article A.Zhen et al. Robust CAR-T memory formation and function via hematopoietic stem cell delivery is published in the journal PLOS Pathogens.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on UCLA materials: Researchers develop more efficient, enduring CAR gene therapy to combat HIV.