ADOPTIVE TRANSFER OF SHIV-SPECIFIC CD8+ T CELLS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV infection is characterized by an inability of the immune system to maintain control of the virus. Experimentally boosting the immune system represents a treatment strategy with the potential to improve the host's ability to control virus. The loss of expression of the co-stimulatory molecule CD28 by CD8+ HIV-specific cells as consequence of differentiation is linked to the inability of CD8 T cells to produce IL-2 as an autocrine proliferation/growth necessary for viral control. Preliminary studies have shown that forcing the expression of CD28 on HIV-specific CD8+ T cell clones confers them the ability to secrete IL-2 upon specific antigen recognition. We predicted that infusing virus-specific CD8+ T cells in vivo might improve persistence and control over viral replication and because such genetic modification of T cells in humans requires evidence of safety, we went on to develop a macaque model and infuse these selected, expanded and genetically modified cells in an autologous macaque. First 108 then 109 cells of both CD8+ CD28+ and CD8+ CD28- subpopulations of the same subclone were infused in a 2-week period. Results from this experiment have shown that the CD28+ population persisted at low levels (0.2-0.6%) of peripheral CD8+ T cells for 6 weeks after transfer then disappeared and that the infusion of cells transiently increased plasma virus in an already viremic macaque. All cells were transduced to express truncated nerve growth factor receptor as a tracking marker. However, the cells rapidly disappeared from the blood potentially due to down-regulation after cell activation. We are determining localization of infused cells in peripheral sites including lymph nodes and gut tissues. The described model offers a unique setting to study the qualitative and quantitative requirements of cellular immunity to maintain control over HIV.