The ability of HIV to establish a long-lived latent infection within resting CD4+ T cells leads to persistence and episodic resupply of the virus in patients treated with antiretroviral therapy (ART), thereby preventing eradication of the disease. Protein kinase C (PKC) modulators such as bryostatin 1 can activate these latently infected cells, potentially leading to their elimination by virus-mediated cytopathic effects, the host’s immune response and/or therapeutic strategies targeting cells actively expressing virus. While research in this area has focused heavily on naturally-occurring PKC modulators, their study has been hampered by their limited and variable availability, and equally significantly by sub-optimal activity and in vivo tolerability. Here we show that a designed, synthetically-accessible analog of bryostatin 1 is better-tolerated in vivo when compared with the naturally-occurring product and potently induces HIV expression from latency in humanized BLT mice, a proven and important model for studying HIV persistence and pathogenesis in vivo. Importantly, this induction of virus expression causes some of the newly HIV-expressing cells to die. Thus, designed, synthetically-accessible, tunable, and efficacious bryostatin analogs can mediate both a “kick” and “kill” response in latently-infected cells and exhibit improved tolerability, therefore showing unique promise as clinical adjuvants for HIV eradication.

HIV在静息CD4 + T细胞内建立长期潜伏感染的能力导致在接受抗逆转录病毒疗法（ART）治疗的患者中病毒的持续存在和发作性补充，从而阻止了疾病的根除。蛋白激酶C（PKC）调节剂（如抑菌素1）可以激活这些潜伏感染的细胞，从而可能通过病毒介导的细胞病变效应，宿主的免疫应答和/或靶向主动表达病毒的细胞的治疗策略来消除它们。尽管该领域的研究主要集中在天然存在的PKC调节剂上，但其研究受到其有限和可变的可用性的阻碍，并且同样受到次优活动和体内的显着影响。耐受性。在这里，我们显示，与天然存在的产品相比，溴索他汀1的设计，合成可及的类似物在体内具有更好的耐受性，并且可以从人源化BLT小鼠的潜伏期中有效诱导HIV表达，这是用于研究HIV持久性和耐药性的可靠且重要的模型体内发病机制。重要的是，这种病毒表达的诱导导致一些新表达HIV的细胞死亡。因此，设计，合成可及，可调性和有效的溴抑他汀类似物可以介导潜伏感染细胞的“踢”和“杀”反应，并表现出更高的耐受性，因此作为根除HIV的临床佐剂具有独特的前景。