Stem cell-based anti-HIV gene therapy

Abstract

Human stem cell-based therapeutic intervention strategies for treating HIV infection have recently undergone a renaissance as a major focus of investigation. Unlike most conventional antiviral therapies, genetically engineered hematopoietic stem cells possess the capacity for prolonged self-renewal that would continuously produce protected immune cells to fight against HIV. A successful strategy therefore has the potential to stably control and ultimately eradicate HIV from patients by a single or minimal treatment. Recent progress in the development of new technologies and clinical trials sets the stage for the current generation of gene therapy approaches to combat HIV infection. In this review, we will discuss two major approaches that are currently underway in the development of stem cell-based gene therapy to target HIV: one that focuses on the protection of cells from productive infection with HIV, and the other that focuses on targeting immune cells to directly combat HIV infection.

Figure 1

Schematic illustrating non-myeloablative HSC-based approaches to treat HIV infection. The anti-HIV factor (such as a siRNA to CCR5 or a molecularly cloned TCR) is cloned and characterized (1) and made into lentiviral vector (or other form enabling genetic transduction of target cells) (2). Stem cells are mobilized from the bone marrow of HIV infected individuals and peripheral blood CD34+ HSCs are obtained by apheresis and cell sorting (3). CD34+ stem cells are then genetically transduced with the anti-HIV factor (4), and the cells are then reinfused back into the individual (5). Following infusion, the anti-HIV gene containing stem cells should migrate to the bone marrow where they take up residence as long-term hematopoietic progenitors. Anti-HIV gene containing cells protected from infection should undergo selection by virus in the body and/or cells engineered to target HIV should respond to the virus and proliferate (6). The effects of this are protection of anti-HIV gene containing cells (7a) or directed targeting of HIV or HIV infected cells by anti-HIV gene expressing cells (7b), resulting in the regeneration of antiviral immune responses and targeted eradication of HIV.