EFFECT OF ANTI-4 1BB ON SIV SPECIFIC CELLULAR IMMUNITY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本提案的目的是确定体内抗4-1BB治疗对恒河猴对SIV疫苗接种和/或感染的细胞免疫应答的影响。在此过程中，我们将探索刺激SIV特异性细胞免疫的新方法，同时确定这种治疗对SIV感染动物病程的影响。4-1BB受体（CDw 137）是在活化T细胞和NK细胞上表达的TNF受体超家族成员，其单克隆抗体在体外和体内优先刺激CD 8 + T细胞。最近的数据表明，CD 8 + T细胞上的4-1BB受体的连接不仅提供了必要的共刺激并因此活化，而且还可以延长其存活。考虑到CD 8 + T细胞在控制HIV和SIV感染中的病毒血症中的重要性，后一种效应是有趣的。因此，该提案解决了该计划公告的重点领域，因为我们可能会确定一种共刺激分子，该分子可能会优化CD 8 + T细胞反应，并最终用作艾滋病毒疫苗的一部分。具体目标是：1）检测抗4-1BB单克隆抗体在体外对猕猴淋巴细胞活化、增殖和细胞因子分泌的影响。2)确定抗4-1BB单克隆抗体对恒河猴接种DNA初免，随后进行改良的安卡拉牛痘（MVA）加强（均编码SIVmac 239基因）诱导的CD 8 + T细胞应答的影响。3)在急性SIVmac 239感染过程中给予抗4-1BB，从而确定治疗对病毒载量、CD 4计数、抗SIV CD 8活性和最终病程的影响

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