Genetic modification of hematopoietic stem cells as a therapy for HIV/AIDS

Abstract

The combination of genetic modification and hematopoietic stem cell (HSC) transplantation may provide the necessary means to develop an alternative treatment option to conventional antiretroviral therapy. As HSCs give rise to all hematopoietic cell types susceptible to HIV infection, modification of HSCs is an ideal strategy for the development of infection-resistant immune cell populations. Although promising results have been obtained in multiple animal models, additional evidence is needed to convincingly demonstrate the feasibility of this approach as a treatment of HIV-1 infected patients. Here, we review the potential of HSC transplantation and the recently identified limitations of this approach. Using the Berlin Patient as a model for a functional cure, we contrast the confines of autologous versus allogeneic transplantation. Finally, we suggest that although autologous, gene-modified HSC-transplantation may significantly reduce plasma viremia, reaching the lower detection limits currently obtainable through daily HAART will remain a challenging endeavor that will require innovative combinatorial therapies.

Figure 1

Pros- and Cons- of Autologous and Allogeneic Transplantation for the treatment of HIV-1 infected patients. Both autologous and allogeneic transplantation studies are currently moving forward in clinical trials. Here, we list several of the potential positive and negative drawbacks of each transplantation procedure. Evidence for the potential successful outcome following allogeneic transplantation has been observed in one HIV-1 infected patient, known as the Berlin Patient, who was successfully cured of HIV following allogeneic transplantation from a CCR5-/- donor. Limited, yet promising studies have suggested that autologous transplantation of genetically modified HSCs may give rise to infection-resistant immune cell populations that in turn may have the capacity to reduce viral pathogenesis. However, studies in murine and nonhuman primates remain inconclusive as plasma viremia has thus far remained readily detectable in animals challenged following transplantation of genetically modified cells.

Figure 2

Autologous Transplantation: Developing an Infection-Resistant Immune System Capable of Controlling Viral Replication. (Top Left Panel) Decrease in latently infected cells following total body irradiation or myeloablative chemotherapy. Studies have shown that although there is a significant reduction in proviral DNA in peripheral blood in HIV-1 infected patients undergoing autologous transplantation while on continuous Highly-Active-Anti-Retroviral Therapy (HAART), HIV remains detectable in the months following hematopoietic stem cell transplantation (HSCT). (Top Right Panel) Genetically modified HSCs give rise to infection-resistant immune cells following successful engraftment. Depending on the method used to render immune cells resistant to infection, genetically modified cells can block HIV-infection regardless of viral tropism. (Bottom Panel) Protected immune cells provide the necessary means to effectively control viral replication in the absence of HAART. CTL and B-cell function are enhanced due to CD4+ T-cell helper function resulting in increased CTL-mediated apoptosis of infected cells and improved neutralization of plasma viremia. Overall immune function is restored and maintained following the cessation of HAART.