Induction of Immunity by Non-Replicating HIV-1

尽管抗逆转录病毒疗法(ART)降低了艾滋病毒的发病率和死亡率 感染，免疫重建不完全，病毒持续存在于组织储存库和反跳性病毒血症 在停止处理时发生。最近的研究发现，间歇性的药物治疗依从性可以 刺激T细胞反应导致了这样一种概念，即通过再次暴露于 病毒，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一种 艺术的附属品。产生人类T细胞反应的一种有效方法是在树突状细胞上递呈抗原 细胞(DC)，一种抗原提呈细胞(APC)系统，可刺激先天和获得性免疫 回应。用活的或化学灭活的(Aldrithiol-2治疗)HIV或SIV有效地冲击DC 体外诱导人类细胞产生HIV特异性的CD4+和CD8+T细胞反应。乙硫醇-2(AT-2) 在不影响病毒粒子表面构象和功能完整性的情况下灭活HIV的感染性 蛋白质。AT-2灭活SIV冲击DC对中国恒河猴病毒血症的长期控制作用 长期感染SIVmac251的猕猴。此外，我们还建立了安全和 树突状细胞在健康个体中的免疫原性，以及最近在HIV+个体中的免疫原性。基于这些 结果，我们将确定AT-2灭活HIV冲击的DC是否诱导治疗性免疫 在一群长期感染艾滋病毒+的人中的反应。具体目标是：(1)优化 人树突状细胞体外捕获、加工和呈递AT-2处理的HIV，作为临床的前奏 研究；(2)开发制备无菌AT-2灭活自体艾滋病毒所需的方法学 在符合法规要求的水平上建立患者的单核细胞；以及(3)建立 自体AT-2灭活HIV冲击的树突状细胞在ART长期抑制中的免疫原性 受感染的HIV+队列。这些研究将有助于确定，当非复制型艾滋病毒在 DC，诱导持久的CD4和CD8应答，有助于控制病毒复制，即使在 艺术的终止。

Although the institution of anti-retroviral 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 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 (Aldrithiol-2 treated) HIV or SIV, efficiently induce HIV-specific CD4+ and CD8+ T cell responses from human cells in vitro. Aldrithiol-2 (AT-2) inactivates HIV infectivity without affecting the conformational and functional integrity of virion surface proteins. DCs pulsed with AT-2 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 AT-2 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 AT-2 treated HIV by human DCs in vitro, as a prelude to clinical studies; (2) develop the methodology required to prepare sterile AT-2 inactivated autologous HIV from patients'monocytes on a level which meets regulatory requirements, and (3) to establish the immunogenicity of DCs pulsed with autologous AT-2 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.