Induction of Immunity by Non-Replicating HIV-1

尽管抗逆转录病毒疗法（ART）的实施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，病毒在组织库中持续存在，并且在停止治疗时发生反弹病毒血症。最近的研究发现，间歇性依从药物治疗可以刺激T细胞反应，这导致了通过再次暴露于病毒的低水平抗原刺激或通过免疫增强T细胞反应的概念，可能有助于控制病毒复制，作为抗逆转录病毒治疗的辅助手段。产生人类CD4+和CD8+ T细胞反应的有效方法是在树突状细胞（dc）上呈递抗原，树突状细胞（dc）是一种抗原呈递细胞（apc）系统，可刺激先天和获得性免疫反应。用活的或化学灭活的（Aldrithiol2处理的）HIV或SIV（猿猴免疫缺陷病毒）脉冲的dc，在体外有效地诱导人类细胞的HIV特异性CD4+和CD8+ T细胞反应。Aldrithiol2 （AT2）在不影响病毒粒子表面蛋白构象和功能完整性的情况下灭活HIV传染性。用AT2灭活SIV脉冲DCs诱导慢性SIVmac251感染的中国恒河猴长期控制病毒血症。此外，我们已经确定了dc在健康个体和最近在HIV+个体中的安全性和免疫原性。基于这些发现，我们将确定AT2灭活HIV脉冲dc是否在慢性感染HIV+个体队列中诱导治疗性免疫反应。具体目标是：(1)优化体外人类dc对AT2治疗HIV的捕获、处理和呈递，作为临床研究的前奏；(2)开发从患者单核细胞制备无菌AT2灭活的自体HIV所需的方法，达到符合监管要求的水平；(3)在抗逆转录病毒抑制的慢性感染HIV+队列中，建立用自体AT2灭活HIV脉冲的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治疗后，非复制性艾滋病毒在dc上递送时，是否会诱导持久的CD4和CD8应答，从而促进控制病毒复制。

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.