The relentless toll on human life from AIDS demands continued research into new strategies for prevention and treatment. Although current treatment strategies have been effective, it is estimated that between 30 to 45% of patients have developed drug-resistant HIV. In consideration of the long-term costs of Highly Active Anti-Retroviral Therapy (HAART) as well as the steady increase in patients developing drug resistant HIV strains, it has become imperative to develop innovative HIV treatments. The main objective of this multi-institutional collaborative program is to develop novel strategies to restore and rebuild an immune system that is resistant to HIV infection by utilizing genetically modified stem cells with anti-HIV retroviral vectors. Our proposal will result in stem cell sources derived from umbilical cord blood (UCB) or human embryonic stem cell lines (hESC) that can eventually be utilized for transplantation directly into patients. These transplanted HIV resistant cells should be protected and used to generate a durable and HIV-resistant immune system. In the short-term, UCB derived stem cells will provide a viable donor cell source. However, it is anticipated that for a long-term solution, hESC will provide a durable donor cell resource that will not depend on collection from a limited neonatal cell source and may be engineered selectively to develop HIV resistant immune systems. The importance of this approach is that it could potentially eradicate cells with latent as well as active HIV and achieve a complete and sustained immune system restoration in HIV infected patients. Thus, it is imperative to develop technologies for successfully protecting cells from HIV infection and also evaluate whether these technologies alter in any way human embryonic stem cells. This proposal will focus on the development and optimization of genes targeting cellular and HIV messages and proteins, thereby disrupting HIV infection by intervening the viral entry and replication in target cells of the immune system. We will examine the efficacy of anti-HIV lentiviral vectors in both hESC and UCB stem cells in order to determine their anti-HIV activity without interfering with cell proliferation and differentiation into hematopoietic cells. Cells harboring the anti-HIV vectors will be evaluated in humanized animal models for HIV resistance and cell maturation to rebuild the immune system. This collaborative proposal capitalizes on our diverse expertise and strong track record in research with hESC, UCB stem cells and HIV therapy. Our goal is to develop the ability to rebuild and restore a robust immune system in HIV infected patients that have been offered little hope of further treatment upon the development of resistance to HAART. This will also provide better insights for developing novel strategies for other immune disorders.
Statement of Benefit to California:
AIDS was first described by Dr. Gottlieb at UCLA in California. Currently, over 150,000 HIV patients live in the State of California. Despite advances in treatment options and research, HIV still poses a major challenge for the health care of Californians. Although Highly Active Anti-Retroviral Therapy (HAART) is effective in many HIV infected patients, challenges of the continuing emergence of drug-resistant HIV, drug toxicity and incomplete viral suppression in about 30 to 45% of patients warrant the development of innovative HIV therapies. Novel strategies to rebuild the competent and functional immune system will be essential to support HIV infected patients. In addition, insights gained into the repair and regeneration of the immune system in HIV infection will be applicable to other diseases and disorders involving immunodeficiency. Proposed studies focus on the use of human umbilical cord blood derived stem cells and human embryonic stem cell lines as a source of stem cells for regenerative medicine translational research and clinical applications with specific emphasis on AIDS. The potential benefits of the proposed studies are following: (1) increased knowledge of novel approaches of HIV therapy, (2) development of new opportunities for cord blood banking and cell processing business, (3) gaining better insights into the regenerative medicine aspects of immunodeficiency syndromes.