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

 描述（由申请人提供）：这是响应R21/R33（TaPHIR）资助机会的新提交资料，该资助机会确定靶向新型免疫抑制途径是否可以耗尽HIV病毒抑制患者中潜伏性HIV感染的CD 4记忆T细胞。虽然高效抗逆转录病毒疗法（HAART）可以抑制HIV复制并显着改善患者的长期健康，但它无法永久清除潜伏的病毒库。因此，需要新的策略来特异性地靶向和破坏潜伏感染的细胞。具有免疫球蛋白和ITIM结构域的T细胞免疫受体（TIGIT）是一种新描述的免疫检查点抑制性受体，其在活化的T细胞和自然杀伤（NK）细胞的亚群上表达，并且发现在肿瘤浸润淋巴结上高度表达。在我们的初步研究中，我们发现在血液中的HIV感染和淋巴组织中的SIV感染期间效应记忆CD 8 + T细胞上的TIGIT和PD-1表达增加，表明TIGIT途径在非人灵长类动物模型中是有活性的。我们正在进行的研究惊人地揭示，TIGIT和PDL-1的双重阻断恢复HIV和SIV效应T细胞功能，表明双重阻断后的有效抗病毒应答可能有助于在再活化后杀死HIV感染的潜伏细胞。随着（1）TIGIT和PDL-1 mAb以及持续且有效地抑制SIV复制的抗逆转录病毒治疗方案的开发，我们提出确定靶向TIGIT和PDL-1免疫抑制途径是否可以耗尽潜伏的HIV和SIV感染的CD 4记忆T细胞，并作为休克和杀死治愈方法中的新型HIV根除方法。在R21阶段，我们提出确定TIGIT和PDL-1阻断在体外增加抗病毒功效并通过增强抗HIV和SIV CD 8 T细胞活性来消耗或消除HIV和SIV潜伏活化细胞的能力。在R33中，我们将测试TIGIT和PDL-1 mAb在HIV的SIV感染恒河猴模型中完全抑制性HAART期间清除潜伏储库的能力。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的治愈或功能性治愈。鉴于我们令人兴奋的初步数据，我们期望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.