Abstract

TUAA0303 - Oral Abstract Session

In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells

Presented by Scott Kitchen (United States).

S. Kitchen, B. Levin, G. Bristol, V. Rezek, S. Kim, C. Aguilera-Sandoval, A. Balamurugan, O. Yang, J. Zack

David Geffen School of Medicine at UCLA, UCLA AIDS Institute, Los Angeles, United States

Background: In HIV infection, the HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication that ultimately fails in its ability to eradicate the virus from the body. Our primary aim is the development of a way to enhance the HIV-specific CTL response to allow long-term viral suppression or viral clearance.
Methods: In our approach, we sought to genetically manipulate human hematopoietic stem cells (HSCs) such that they differentiate into mature CTLs that will kill HIV infected cells. To perform this, we utilized molecularly cloned HIV-specific T cell receptors (TCRs) derived from CD8+ T cells. These TCRs were used to genetically transduce HSCs that were introduced into a humanized mouse and were allowed to differentiate into mature human CD8+ CTLs. Mice expressing the transgenic HIV-specific TCR and, separately, control mice were then infected with HIV-1 and functional cellular responses, viral suppression, and viral and T cell dynamics were assessed.
Results: We found that genetic modification of human HSCs with a cloned TCR allows proper differentiation of the cells to occur in vivo and these cells migrate to multiple anatomic sites, mimicking what is seen in humans. We observed that the genetically modified HIV-specific CTLs form a functional antiviral response in vivo that results in the significant suppression of HIV replication in multiple organs. In addition, we found significant correlations between the levels of reconstitution with cells bearing the HIV-specific TCR, antigen-driven T cell expansion, and the control of viral replication.
Conclusions: We have developed a system to closely characterize the engineering of antiviral immunity and HIV-specific CTL responses. Our results strongly suggest that stem cell based gene therapy may be a feasible approach in the treatment of chronic viral infections and provide a foundation towards the development of this type of strategy.