Reactivation of latent HIV through TLR signaling

描述（由申请人提供）：HIV感染细胞的潜伏储库的存在构成了病毒根除的主要障碍。HIV-1潜伏库很小，但寿命极长。潜伏性感染与检测不到的病毒基因表达水平相关，并且似乎是非细胞病变的。然而，在重新激活后，潜伏病毒进入活跃的复制模式，在这种模式下，它们完全有能力传播和诱导疾病。该领域目前的想法是，将能够重新激活潜伏病毒的假想药物（“抗潜伏”药物）与当今的抗逆转录病毒药物相结合，将是根除病毒的有效方法。 Pam 3C-SK 4是革兰氏阴性菌、分枝杆菌和一些革兰氏阳性菌中天然存在的脂蛋白的合成三酰化脂肽类似物;并且其用作TLR-2/1活化的参比化合物。使用先前描述的用于研究HIV-1潜伏期的原代细胞模型，我们发现三酰化脂肽Pam 3C-SK 4，而不是测试的其他TLR激动剂，能够诱导病毒再活化形成中央记忆CD 4 T细胞中的潜伏期。我们的主要目标是了解由Pam 3C-SK 4激活的信号通路，该信号通路导致病毒从CD 4记忆T细胞中的潜伏期重新激活。此外，我们将研究Pam 3C-SK 4是否增加对病毒刺激后凋亡诱导的易感性或加速凋亡诱导的动力学，以及Pam 3C-SK 4诱导细胞凋亡的能力。 消除或减少体外潜在储库。这些研究将增加我们对病毒再激活机制的了解，这些机制可应用于根除HIV-1的新治疗策略。

DESCRIPTION (provided by applicant): The existence of latent reservoirs of HIV-infected cells constitutes the major impediment towards viral eradication. HIV-1 latent reservoirs are small, but extremely long-lived. Latent infection is associated with undetectable levels of viral gene expression and appears to be non-cytopathic. However, upon reactivation, latent viruses enter an active mode of replication in which they are fully competent for spread and induction of disease. The current thinking in the field is that a combination of hypothetical drugs that will reactivate latent viruses (''anti-latency'' drugs), with present-day antiretroviral drugs, will be n effective approach toward viral eradication. Pam3C-SK4 is a synthetic triacylated lipopeptide analogue of naturally occurring lipoproteins in gram- negative bacteria, mycobacteria and some gram-positive bacteria; and it is used as a reference compound for TLR-2/1 activation. Using a previously described primary cell model for the study of HIV-1 latency, we have found that the triacylated lipopeptide Pam3C-SK4, but not other TLR agonists tested, is able to induce viral reactivation form latency in central memory CD4 T cells. Our main goal is to understand the signaling pathway activated by Pam3C-SK4 that leads to viral reactivation from latency in CD4 memory T cells. Furthermore, we will study whether Pam3C-SK4 increases the susceptibility to or accelerate the kinetics of apoptosis induction upon virus stimulation, as well as the ability to eliminate or reduce the latent reservoir in vitro. These studies will increase our knowledge on mechanisms of viral reactivation that can be applied to new therapeutic strategies toward HIV-1 eradication.