The human immunodeficiency virus (HIV) remains a major source of morbidity, mortality, and healthcare costs worldwide. In 2011 alone, 34 million people were living with HIV, with 2.5 million new infections and 1.7 million deaths. Although antiretroviral therapy (ART) can drastically reduce viremia in HIV patients, ART must be continued throughout life, or else the virus rebounds from latently infected cells. Without a cure, the necessity of lifelong adherence to ART presents challenges of cost, toxicity, adverse interactions, and resistance. Recently, there have been several cases of HIV patients who underwent bone marrow transplant (BMT) and have shown a lack of viral rebound after discontinuing ART. One patient in Berlin received an allogeneic BMT from a donor who was homozygous for the HIV-resistant CCR5delta32 mutation, and two patients in Boston received allogeneic BMTs from CCR5-wildtype donors. The mechanism of possible cure in these patients has not been established, but an important similarity is that they all received allogeneic BMTs from unrelated donors. In cancer research, allogeneic BMTs and donor lymphocyte infusions (DLI) have been shown to reduce incidence of relapse in leukemia patients, likely due to a graft-versus-leukemia effect in which the donor immune cells recognize and clear the host's leukemic cells. One leading hypothesis in the Berlin and Boston patients is that a similar graft-versus-host effect occurred in which the donor immune cells recognized and cleared the host's HIV-infected cells, thus resulting in eradication of the HIV reservoir and cure. This proposal outlines specific aims to test this hypothesis using the humanized BLT mouse model developed in our laboratory. BLT mice are """"""""humanized"""""""" by reconstitution with human hematopoietic cells, and they recapitulate key features of HIV infection, pathogenesis, suppression, and latency as seen in humans. The BLT mouse is thus an excellent model to investigate clearance of HIV-infected cells, and I will examine the graft-versus-host effect directly with allogeneic human DLI. These experiments will (1) evaluate the engraftment of allogeneic human DLI in already-humanized BLT mice and the clearance of existing human cells, particularly CD4+ T cells (primary HIV target cells) and resting CD4+ T cells (primary latently infected cells), and (2) evaluate the effet of allogeneic human DLI on HIV-infected cells in already-humanized HIV-infected BLT mice. If funded, this project will investigate a potential mechanism for curing HIV and will inform the future development of cure strategies, using an advanced humanized mouse model to perform experiments and analyses that would be impractical or unethical in human subjects. Along with the superb environment at UNC Chapel Hill, excellent mentoring by Dr. Garcia, and a well-rounded training plan, this research will provide a solid foundation on which I can continue my predoctoral training toward a career as a physician-scientist in the fields of immunology and infectious disease.
There is no cure yet available for HIV infection, but recent cases of possible cures in HIV patients who received bone marrow transplants suggest that donor cells may be able to clear the host's HIV-infected cells through a graft-versus-host effect. This project will evaluate this graft-versus-host effect on HIV infection in an advanced humanized mouse model, and the results of this work will inform future studies and strategies toward an HIV cure.
|Tsai, Perry; Wu, Guoxin; Baker, Caroline E et al. (2016) In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection. Retrovirology 13:36|
|Tsai, Perry; Thayer, William O; Liu, Liqin et al. (2016) CD19xCD3 DART protein mediates human B-cell depletion in vivo in humanized BLT mice. Mol Ther Oncolytics 3:15024|