R5 SHIV/MACAQUE MODEL FOR THE EVALUATION OF T AND B CELL-BASED HIV-1 VACCINE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们最近报道了晚期R5嗜性SHIVSF162P3N分离株静脉感染印度(IND)RMS时，病毒复制水平高，肠道相关淋巴组织(GALT)中的急性CD4+T细胞耗尽，以及辅受体开关。为了更接近于HIV-1在人类中的常见传播模式，我们检查了SHIVSF162P3N通过直肠途径的感染。在初步研究中，我们发现带有R5SHIVSF162P3N的Ind RMS粘膜感染概括了人类HIV-1感染的关键病原学特征，包括肠道内急性CD4+T细胞耗尽，不受控制的复制，以及通过切换辅助受体偏好而进展为艾滋病。在SHIVSF162P3N IV和IR感染的猕猴身上看到的高设定点病毒血症和致病性的一致性使我们假设，这个动物模型系统不仅对于深入研究体内协同受体偏好变化的进化过程和潜在机制非常重要，而且对于促进刺激免疫系统的两个效应器手臂的HIV-1候选疫苗的发现也具有重要意义。

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. We recently reported high levels of virus replication, acute CD4+ T cell depletion in the gut associated lymphoid tissues (GALT), and coreceptor switch in Indian (Ind) RMs infected intravenously (IV) with the late R5 tropic SHIVSF162P3N isolate. To more closely mimic the common modes of transmission of HIV-1 in humans, infection though the rectal route of SHIVSF162P3N was examined. In Preliminary studies, we show that mucosal infection of Ind RMs with R5 SHIVSF162P3N recapitulates key pathogenic features of HIV-1 infection in humans including acute CD4+ T cell depletion in the gut, uncontrolled replication, and progression to AIDS with switch in coreceptor preference. The consistency of high setpoint viremia and pathogenicity seen in SHIVSF162P3N IV and IR infected macaques leads us to hypothesize that this animal model system will be highly relevant not only for in-depth studies of the evolutionary process and the underlying mechanism for the change in coreceptor preference in vivo, but also for advancing the discovery of HIV-1 candidate vaccines that stimulate both effector arms of the immune system.