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. The intent of this proposal is to ascertain the effect of in vivo anti-4-1BB treatment on rhesus macaque cellular immune responses to SIV vaccination and/or infection. In so doing, we will explore new ways to stimulate SIV-specific cellular immunity and at the same time, determine the effect of this treatment on the course of disease in SIV-infected animals. Monoclonal antibodies to the 4-1BB receptor (CDw137), a member of the TNF receptor superfamily expressed on activated T cells and NK cells, preferentially stimulate CD8+ T cells in vitro and in vivo. Recent data suggests that ligation of the 4-1BB receptor on CD8+ T cells not only provides necessary co-stimulation and thus activation but may also prolong their survival. The latter effect is intriguing given the importance of CD8+ T cells in controlling viremia in both HIV and SIV infections. This proposal therefore addresses the areas of emphasis of the program announcement in that we are potentially identifying a co-stimulator that may optimize the CD8+ T cell response and ultimately be used as part of a vaccine against HIV.
The specific aims are: 1) To test the in vitro effect of anti-4-1BB monoclonals on macaque lymphocytes in terms of activation, proliferation and cytokine secretion. 2) To determine the effect of anti-4-1BB monoclonals on CD8+ T cell responses induced by vaccination of Rhesus macaques with a DNA prime followed by a modified vaccinia Ankara (MVA) boost, both encoding SIVmac239 genes. 3) To administer anti-4-1BB during the course of an acute SIVmac239 infection and thus determine the effect of the treatment on viral loads, CD4 counts, anti-SIV CD8 activity and ultimately disease cours
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