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The latest advances in gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for HIV infection. Currently, HIV-specific CARs are being applied to peripheral T cells, NK cells, and stem cells to enhance the ability to recognize and kill HIV-infected cells. At Creative Biolabs, we have a thorough understanding of the important aspects of anti-HIV CAR T cell development and provide a variety of new generation HIV directed CARs, such as anti-HIV CAR T cells, anti-HIV CAR NK cells, and HSPC-derived HIV CARs to support the cellular immunotherapy development of HIV infection.
1. Anti-HIV CAR-T cells
Compared with retroviral vector engineering that introduces other cell types that are at risk of oncogenic transformation, CAR-modified T cell products are more stable and have lower risks, especially for HIV patients who need long-term adherence to treatment. Significant improvements have been achieved by incorporating new and improved promoters and costimulatory domain elements and replacing early gamma retrovirus-based gene therapy vectors with HIV-based lentiviral backbones, which facilitates integration into the open reading frame.
The main obstacle to any therapy against HIV is the inability to demonstrate efficacy in the persistent sites of the virus in the tissue. Although reports indicate that CAR T cells have anti-reactivation functions, few studies have identified anti-HIV CAR T cells in reservoir tissues and/or their ability to target latently infected cells in vivo. The addition of chemokine receptors can improve transport: for example, the co-expression of CCR7 chemokine receptors, or CXCR5 can improve the trafficking of CAR T cells to B cell follicles.
2. Anti-HIV CAR-NK cells
In addition to autologous CAR-T products, genetically modified NK cells are now considered to be one of the most interesting and innovative candidates in the preclinical research of cellular immunotherapy. These cells belong to the innate immune system and can mediate anti-tumor effects without the risk of developing host-targeted transplant disease (GvHD). Therefore, NK cells are suitable for allogeneic therapy, allowing a large number of individuals affected by cancer to be treated starting from a single batch produced from a healthy donor. This allows overcoming the limitations associated with personalized autotherapy, with significant benefits from both a technical and economic point of view.
Although the life span of mature NK cells is limited from a few days to a few weeks, the use of immature NK cells (such as derived from cord blood, induced pluripotent stem cells (iPSC), or human embryonic stem cells (hESC)) can improve their lifespan and persistence in vivo. In particular, the self-renewal properties of iPSC cells can provide an unlimited number of T cells or NK cells that can establish a memory phenotype.
3. Anti-HIV CAR-HPSC
Delivery of CAR-encoding gene therapy vectors to hematopoietic stem cells and progenitor cells (HPSC) can combine CAR-T, -NK, and other hematopoietic cells against the target antigen. This method can solve several challenges encountered by CAR T cells. First, HSPC-derived CAR cells may be transported to tissues more efficiently than CAR T cells, for example, by differentiation into mature cells that can cross anatomical and physiological barriers. Second, even in the absence of strong antigen expression, HSPC-derived CAR cells still exist. Finally, thymus selection should eliminate self-reactive T cells and improve the safety of this strategy compared to CAR T cells.
HSC (CD34+) from a healthy donor are engineered using viral vectors that insert the CAR sequence in the cell genome
The CAR-HSCS differentiate in T/NK cells, resulting in a population of CAR-NK and CAR-T that can be used for multiple patients
The CAR-T/NK infused in the patient selectively recognize the HIV infected cells expressing the HIV antigen and mediate the killing
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