TLR Therapy to Eradicate the SIV Reservoir

 描述(申请人提供)：从感染者身上根除人类免疫缺陷病毒(HIV-1)是抗逆转录病毒治疗(ART)的最终目标。随着ART养生法的出现，在这方面取得了重大进展。尽管在ART方案中，感染患者的血浆病毒血症持续抑制在可检测到的限度以下两年或更长时间，但仍可从宿主内的各种补液中恢复具有复制能力的病毒，最显著的是长寿命静止记忆CD4+T淋巴细胞。这些和其他未知的病毒库是根除艾滋病毒感染的最后障碍。尽管抗逆转录病毒治疗仍然是治疗的黄金标准，但即使是强化治疗方案也不会影响病毒库。因此，必须探索替代治疗策略。使用“休克和杀死”方案可能是扰乱艾滋病毒宿主和加强病毒清除或控制的重要方法。然而，在我们对这些组合模式的理解上有很大的差距，这不容易通过对人类患者的研究来确定。使用我们的恒河猴(RM)SIV持久性模型(Whitney等人)。自然2014)，我们建议继续评估我们已经发现的可以有效地从潜伏期重新激活SIV和HIV的TLR7激动剂。这种新型病毒潜伏期反转剂是口服的，与HDACi形成鲜明对比的是，它显著增强了抗病毒免疫反应。我们建议在有效ART的背景下确定TLR7激动剂影响已建立的解剖储存库的机制。为了研究这些假说，我们提出了以下具体目标：1.确定早期ART和LRAS(TLR7)对解剖组织中SIV储存库的影响。2.确定TLR7治疗对T细胞和单核/巨噬细胞系SIV储存库构成的影响。3.确定TLR7诱导的马猴A*01/A*02停止抗逆转录病毒治疗后对SIV储备库的免疫调控的免疫学相关性。

 DESCRIPTION (provided by applicant): The eradication of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy (ART). Major advances have been made towards this end with the advent of ART regimens. Despite the sustained suppression of plasma viremia below detectable limits in infected patients for 2 or more years on ART regimens, replication competent virus can still be recovered from a variety of subterfuges within the host, most notably long-lived quiescent memory CD4+ T lymphocytes. These and other unknown viral reservoirs represent the final impediment to the eradication of HIV infection. Although ART remains the gold standard of care, even intensified regimens do not impact the viral reservoir. Therefore, alternative therapeutic strategies must be explored. The use of "shock and kill" regimens might be a significant approach to perturb the HIV reservoir and enhance viral clearance or control. However, there are significant gaps in our understanding of these combinatorial modalities that cannot be easily ascertained by the study of human patients. Using our rhesus monkey (RM) model of SIV persistence (Whitney et al. Nature 2014), we propose to continue to evaluate a TLR7 agonist that we have discovered can potently reactivate SIV and HIV from latency. This new class of viral latency reversing agent is orally deliverable, and in stark contrast to HDACi, markedly potentiates antiviral immune responses. We propose to determine the mechanisms by which TLR7 agonists can impact established anatomic reservoirs in the setting of potent ART. To investigate these hypotheses, we propose the following Specific Aims: 1. Determine the impact of early ART and LRAs (TLR7) upon the SIV reservoir in anatomic tissues. 2. Determine the impact of TLR7 treatment upon the constitution of the SIV reservoir in T cell and monocyte/macrophage lineages. 3. Determine the immunologic correlates of TLR7 induced immune control on the SIV reservoir after cessation of ART in Mamu A*01/A*02 monkeys.