Induction of Immunity by Non-Replicating HIV-1

虽然抗逆转录病毒疗法(ART)降低了艾滋病毒感染的发病率和死亡率，但免疫重建不完全，病毒持续存在于组织储存库，治疗停止时会发生反跳性病毒血症。最近的研究发现，间歇性药物治疗可以刺激T细胞反应，这导致了这样的概念，即通过再次接触病毒进行低水平的抗原刺激，或通过免疫增强T细胞反应，可能有助于控制病毒复制，作为ART的辅助手段。产生人类CD4+和CD8+T细胞反应的一种有效方法是在树突状细胞(DC)上递呈抗原，树突状细胞(DC)是一种抗原提呈细胞(APC)系统，可以刺激先天性和获得性免疫反应。用活体或化学灭活(Aldrithiol2处理)的HIV或SIV(猿猴免疫缺陷病毒)冲击的DC，在体外有效地从人类细胞中诱导HIV特异性的CD4+和CD8+T细胞反应。Aldrithiol2(AT2)在不影响病毒粒子表面蛋白的构象和功能完整性的情况下灭活HIV的感染性。用AT2灭活SIV冲击的DC诱导慢性感染SIVmac251的中国恒河猴病毒血症的长期控制。此外，我们还证实了DC在健康个体中的安全性和免疫原性，最近在HIV+个体中也是如此。基于这些发现，我们将确定AT2灭活HIV冲击的DC是否在一组慢性感染HIV+的个体中诱导治疗性免疫反应。其具体目的是：(1)优化人类DC体外捕获、处理和呈现AT2处理的艾滋病毒，作为临床研究的前奏。(2)开发从患者单核细胞中制备无菌AT2灭活的自体艾滋病毒所需的方法学，以满足法规要求，以及(3)在ART抑制的、慢性感染的艾滋病毒+队列中建立冲击自体AT2灭活艾滋病毒的DC的安全性和免疫原性。这些研究将有助于确定，即使在终止抗逆转录病毒疗法后，非复制型艾滋病毒在DC上传递时，是否会诱导持久的CD4和CD8反应，从而促进病毒复制的控制。

Although the institution of antiretroviral therapy (ART) has reduced morbidity and mortality from HIV infection, immune reconstitution is incomplete, virus persists in tissue reservoirs and rebound viremia occurs when treatment is halted. Recent findings that intermittent compliance with drug therapy can stimulate T cell responses has led to the concept that low-level antigenic stimulation through re-exposure to virus, or boosting of T cell responses via immunization, may facilitate control of viral replication as an adjunct to ART. An effective way to generate human CD4+ and CD8+ T cell responses is by presenting antigens on dendritic cells (DCs), a system of antigen presenting cells (APCs) that stimulate innate and acquired immune responses. DCs pulsed with live or chemically inactivated (Aldrithiol2 treated) HIV or SIV (simian immunodeficiency virus), efficiently induce HIV-specific CD4+ and CD8+ T cell responses from human cells in vitro. Aldrithiol2 (AT2) inactivates HIV infectivity without affecting the conformational and functional integrity of virion surface proteins. DCs pulsed with AT2 inactivated SIV induced long-term control of viremia in Chinese rhesus macaques chronically infected with SIVmac251. Furthermore, we have established the safety and immunogenicity of DCs in healthy individuals and more recently in HIV+ individuals. Based on these findings, we will determine whether DCs pulsed with AT2 inactivated-HIV induce therapeutic immune responses in a cohort of chronically infected HIV+ individuals. The specific aims are to: (1) optimize the capture, processing and presentation of AT2 treated HIV by human DCs in vitro, as a prelude to clinical studies; (2) develop the methodology required to prepare sterile AT2 inactivated autologous HIV from patients’ monocytes on a level which meets regulatory requirements, and (3) to establish the safety and immunogenicity of DCs pulsed with autologous AT2 inactivated HIV in an ART suppressed, chronically infected HIV+ cohort. These studies will help determine whether non-replicating HIV, when delivered on DCs, induces durable CD4 and CD8 responses which facilitate control of viral replication, even after termination of ART.