Engineering HIV-Specific T Cell Immunity

Scott Kitchen, University of California Los Angeles
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)

HIV infection results in life-long persistence of the virus as the immune response fails to effectively clear HIV from the body. Since there are no effective ways, either through drug treatment or through vaccination, to rid the virus in infected individuals, there is a strong need for an alternative strategy to enhance the immune response towards HIV. Through genetic manipulation of a particular type of human stem cells, immune cells can be engineered to combat viral infections. In our preliminary studies, we determined that the genetic modification of human blood stem cells with a key molecule involved in immune killer cell recognition of HIV infected cells, an HIV-specific T cell receptor, allows the production of mature T cells that can directly target and kill HIV infected cells. These results suggest that genetic engineering via stem cells may allow tailoring of cells involved in the immune response to battle HIV infection. In order for a strategy of genetically modifying stem cells to produce HIV-specific killer cells to be an effective clinical therapy, greater understanding of the role of molecularly cloned T cell receptors in producing these cells is necessary. This proposal seeks to molecularly clone a diversity of HIV specific human T cell receptors that can direct stem cells to become mature HIV-specific killer cells. We will characterize the development of stem cells that are genetically modified with these T cell receptors and their ability to recognize and kill HIV infected cells. We will further examine if the modification of a cellular protein involved in muting the HIV-specific T cell response in infected individuals will allow enhanced HIV-specific cellular immune responses with these genetically modified cells. In all, these studies will provide the foundation towards developing a therapeutic strategy that will allow the direct genetic programming of the immune response to combat and clear HIV infection from the body.