ASSESSMENT OF PD-I BLOCKADE AS A NEW IMMUNOTHERAPEUTIC APPROACH TO AIDS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：探讨PD-1受体阻断剂对SIV感染恒河猴稳定期T细胞动力学和功能、免疫激活和病毒复制的影响。 假设：阻断体内细胞激活抑制通路PD-1/PD-L1将增强T细胞的激活、增殖和功能，从而更好地控制病毒血症，改善整体T细胞功能和动态平衡，而不会明显触发失衡的免疫激活。 理论基础和意义：PD-1在HIV特异性T细胞上上调，表达水平与病毒载量以及HIV特异性CD8 T细胞细胞因子产生和增殖能力的降低显著相关。在体外阻断PD-1/PD-L1通路可增强HIV特异性CD8 T细胞的增殖能力，并导致细胞因子和细胞毒分子的产生增加，以应对同源AGS。我们最近也报道了PD-1的表达水平与SIV特异性T细胞的功能水平相关。此外，我们的初步结果表明，在病毒感染后，记忆中PD-1的表达水平也比NA？ve B细胞上调。此外，人类抗PD-L1抗体(Medarex，MDX-1105)被证明可以增强T细胞的激活和增殖，最近被批准用于晚期或复发实体肿瘤患者的第一阶段临床试验。基于这些发现，我们假设在体内阻断PD-1/PD-L1相互作用将显著增强SIV特异性T细胞的活性、功能和增殖。值得注意的是，用抗PD-1抗体治疗小鼠被证明是耐受的(安全的)和 不会引起毒性免疫激活。这种方法预计将提高对SIV/HIV慢性感染的免疫力，因此将对这些病毒的治疗/疫苗接种产生深远影响。这项研究是在去年完成的，研究表明，在感染SIV的猴子中，注射抗PD-1抗体可以短暂地增加CD4记忆T细胞的再生和功能，并使CD4+和CD8+记忆T细胞的基因表达模式正常化。这些数据已被用于寻求NIH的长期资金，以进一步探索这些发现的机制和生物学意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Purpose: To assess the effect of PD-1 blockade on T cell dynamics and function, immune activation and viral replication in SIV-infected rhesus macaques in stable plateau phase. Hypothesis: Blocking the cellular activation inhibitory pathways PD-1/PD-L1 in vivo will enhance T cell activation, proliferation, and function resulting in better control of viremia and improved overall T cell function and homeostasis without significant triggering of unbalanced immune activation. Rationale and Significance: PD-1 is upregulated on HIV-specific T cells, and expression levels are significantly correlated with both viral load and the reduced capacity of cytokine production and proliferation of HIV-specific CD8 T cells. Blocking the PD-1/PD-L1 pathway in vitro enhanced the capacity of HIV-specific CD8 T cells to proliferate and led to an increased cytokine and cytotoxic molecules production in response to cognate Ags. We have also recently reported that PD-1 level of expression correlates with the level of functionality of SIV-specific T cells. Moreover, our preliminary results indicated that PD-1 level of expression was also upregulated on memory compared to na¿ve B cells following viral infections. In addition, human anti-PD-L1 antibody (Medarex, MDX-1105), shown to enhance T cells activation and proliferation, was recently approved for Phase 1 clinical trial involving patients with advanced or recurrent solid tumors. Based on these findings, we hypothesized that in vivo blocking of PD-1/PD-L1 interaction would significantly enhance the activity, function, and proliferation of SIV-specific T cells. Of note, treating mice with anti-PD-1 was proven to be tolerated (safe) and did not induce toxic immune activations. This approach is expected to boost immunity against SIV/HIV chronic infection and would, hence, have a profound impact on treatment/vaccination against these viruses. This work was completed in the last year and revealed that administration of anti-PD-1 transiently increased the regeneration and function of CD4 memory T cells in SIV-infected monkeys, as well as normalized the gene expression pattern of both CD4+ and CD8+ memory T cells. These data have been used to seek long-term NIH funding to further explore the mechanisms and biologic implication of these findings.