Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System

“…20,47,54 This strategy was used, for example, to generate human immunodeficiency virus (HIV)-specific CAR T cells that were resistant to HIV-1 infection by targeting the integration of the CAR into the CCR5 locus, which codes for the co-receptor used by HIV to enter the cells. 55 Of particular interest is the targeted integration of a CAR transgene into TCR encoding loci. Such a strategy has been employed to place the CAR under control of the TRAC promoter and thus ensure ''physiological'' expression.…”

HIV Receives a “One Two Knockout Punch”

“…Moreover, advances in gene-editing technology hold the promise that T cell potency can be enhanced by gene modification, deletion, or addition. 1 In this issue of Molecular Therapy, Hale et al, 2 in a single construct, combine CCR5 knockdown with a chimeric antigen receptor targeting the HIV envelope, a combination strategy that can potentially provide both anti-HIV activity independent of major histocompatibility complex (MHC) expression and protection of gene-modified T cells from HIV infection.…”

“…11 Nevertheless, results from the HIV CAR T cell studies and studies utilizing zinc finger nuclease approaches to knock down CCR5 suggest that combining these two modifications to produce a T cell therapeutic that has potent anti-HIV activity and is resistant to HIV infection is highly desirable. 9 In this issue of Molecular Therapy, Hale et al 2 present a glimpse into how such a product might look. Using HDR, their work describes directed delivery of a second generation CAR based off broadly neutralizing antibodies specific for the HIV envelope glycoprotein into the CCR5 locus (see Figure 1).…”

“…They introduce their transgene through an AAV donor template and show that modified cells are capable of suppressing HIV viral replication in vitro when compared to cells transduced with a control CAR (CD19-CAR). 2 Four days after coculture with peripheral blood mononuclear cells (PBMCs) containing actively replicating HIV, T cells modified with the PGT145-CAR and a CCR5 disruption had lower measurable viral particles (using the p24 ELISA as the readout) compared to T cells transduced with PGT145 CAR T cells and an intact CCR5. 2 This novel T cell therapeutic, therefore, has the potential to be resistant to HIV infection and highly potent against HIV.…”

“…2 Four days after coculture with peripheral blood mononuclear cells (PBMCs) containing actively replicating HIV, T cells modified with the PGT145-CAR and a CCR5 disruption had lower measurable viral particles (using the p24 ELISA as the readout) compared to T cells transduced with PGT145 CAR T cells and an intact CCR5. 2 This novel T cell therapeutic, therefore, has the potential to be resistant to HIV infection and highly potent against HIV. The caveat is that the studies presented were all carried out in vitro.…”