Reversal of Adaptive Immune Dysfunction in Shock and Kill HIV Cure Strategies

 描述(由申请人提供)：这是对R21/R33(TaPHIR)资助机会的新提交，该机会确定了针对一种新的免疫抑制途径是否可以耗尽HIV病毒抑制患者中潜伏的HIV感染的CD4记忆T细胞。虽然高效抗逆转录病毒疗法(HAART)可以抑制艾滋病毒复制，显著改善患者的长期健康，但它无法永久消除潜在的病毒储备库。因此，需要新的策略来专门针对和摧毁潜伏感染的细胞。具有免疫球蛋白和ITIM结构域的T细胞免疫受体(TIGIT)是一种新发现的免疫检查点抑制受体，表达于活化的T细胞亚群和自然杀伤细胞(NK细胞)上，并在肿瘤浸润性淋巴结高表达。在我们的初步研究中，我们发现在血液中感染HIV和淋巴组织中SIV感染的过程中，效应记忆CD8+T细胞上TIGIT和PD-1的表达增加，表明TIGIT途径在非人类灵长类动物模型中是活跃的。我们正在进行的研究表明，TIGIT和PDL-1的双重阻断可以恢复HIV和SIV效应器T细胞的功能，这表明双重阻断后的有效抗病毒反应可能有助于在重新激活后杀死HIV感染的潜伏细胞。随着(1)TIGIT和PDL-1单抗的发展以及持续有效地抑制SIV复制的抗逆转录病毒治疗方案的发展，我们建议确定靶向TIGIT和PDL-1免疫抑制途径是否可以耗尽潜伏感染HIV和SIV的CD4记忆T细胞，并在休克和杀伤性治疗方法中作为一种新的HIV根除方法。在R21期，我们建议通过增强抗HIV和SIV CD8 T细胞的活性来确定TIGIT和PDL-1阻断在体外提高抗病毒效果以及耗尽或灭活HIV和SIV潜伏激活细胞的能力。在R33中，我们将在SIV感染的恒河猴HIV模型中测试TIGIT和PDL-1单抗在完全抑制HAART期间清除潜伏库的能力。这些研究是迈向一种新方法的第一步，这种方法将导致持续治愈或功能治愈。鉴于我们令人兴奋的初步数据，我们预计研究能力将达到该项目中概述的里程碑。

 DESCRIPTION (provided by applicant): This is the new submission in response to an R21/R33 (TaPHIR) funding opportunity determining whether targeting a novel immune-inhibitory pathway can deplete latently HIV infected CD4 memory T cells in HIV virally suppressed patients. Although highly active antiretroviral therapy (HAART) can suppress HIV replication and significantly improve the long-term health of the patient, it is unable to permanently remove latent reservoirs of virus. Therefore, novel strategies are needed to specifically target and destroy latently infected cells. The T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a newly described immune checkpoint inhibitory receptor expressed on subsets of activated T cells, and natural killer (NK) cells and found highly expressed on tumor infiltrating lymph nodes. In our preliminary studies we find increased TIGIT and PD-1 expression on effector memory CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue indicating that the TIGIT pathway is active in the non-human primate model. Our ongoing studies, reveal strikingly, that dual blockade of TIGIT and PDL-1 restores HIV and SIV effector T cell function indicating that potent anti-viral responses following dual blockade may aid in the killing of HIV-infected latent cells following reactivation. With the development of (1) TIGIT and PDL-1 mAbs and an anti-retroviral therapy regimen that consistently and potently inhibits SIV replication, we propose to determine whether targeting the TIGIT and PDL-1 immune-inhibitory pathway can deplete latently HIV and SIV infected CD4 memory T cells and serve as a novel HIV eradication approach in shock and kill cure approach. In the R21 phase we propose to determine the ability of TIGIT and PDL-1 blockade to increase antiviral efficacy in vitro and deplete or inactivate HIV and SIV latently activated cells by enhancing anti-HIV and SIV CD8 T cell activity. In the R33 we will test the ability of TIGIT and PDL-1 mAbs to clear the latent reservoir during fully suppressive HAART in the SIV infected rhesus macaque model of HIV. These studies are the first steps towards a novel approach that will lead to a sustained cure or functional cure. Given our exciting preliminary data, research capabilities we expect to reach the milestones outlined in this project.