TLR Immunotherapy to Eradicate Anatomic SIV Reservoirs

摘要 从受感染的个体中根除人类免疫缺陷病毒（HIV-1）是 抗逆转录病毒疗法（ART）。随着抗逆转录病毒疗法的出现，在这方面取得了重大进展 养生法尽管在感染患者中血浆病毒血症持续抑制在可检测的限度以下， 接受ART治疗2年或更长时间后，仍可以从各种组织中回收有复制能力的病毒。 宿主内的托词，最明显的是长寿命的静态记忆CD 4 + T淋巴细胞。这些和其他 未知的病毒储库是根除HIV感染的最后障碍。 尽管ART仍然是护理的黄金标准，但即使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”方案可能是一个 这是干扰HIV储存库和增强病毒清除或控制的重要方法。但有 我们对这些组合模式的理解存在重大差距，这些差距无法通过 人类患者的研究。使用我们的SIV持续性的恒河猴（RM）模型（Whitney等人，Nature 2014），我们建议继续评估我们已经发现可以有效地重新激活SIV的TLR 7激动剂 和HIV-1的潜伏期。这种新型病毒潜伏期逆转剂可以口服，并且在斯塔克 与HDACi相反，显著增强抗病毒免疫应答。我们建议确定 TLR 7激动剂可在有效ART的背景下影响已建立的解剖储库的机制。 为了研究这些假设，我们提出以下具体目标： 1.确定早期ART和LRA（TLR 7）对解剖组织中SIV储库的影响。 2.确定TLR 7处理对T细胞中SIV储库的构成的影响， 单核细胞/巨噬细胞谱系。 3.确定TLR 7诱导的免疫控制对SIV储库的免疫学相关性， 在Mamu A*01/A*02猴中停止ART。

ABSTRACT 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-1 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.