Induction of Immunity by Non-Replicating HIV-1

虽然抗逆转录病毒疗法的建立降低了艾滋病毒的发病率和死亡率， 感染、免疫重建不完全、病毒在组织储库中持续存在和反弹性病毒血症 当治疗停止时发生。最近的研究发现，间歇性药物治疗的依从性， 刺激T细胞应答导致了这样的概念，即通过再次暴露于 病毒，或通过免疫增强T细胞应答，可以促进控制病毒复制， 产生人T细胞应答的一种有效方式是通过在树突状细胞上呈递抗原， 细胞（DC），一种刺激先天性和获得性免疫的抗原呈递细胞（APC）系统， 应答用活的或化学灭活的（Aldrithiol-2处理的）HIV或SIV脉冲的DC，有效地 在体外从人细胞诱导HIV特异性CD 4+和CD 8 + T细胞应答。醛硫醇-2（AT-2） 灭活HIV感染性，而不影响病毒体表面的构象和功能完整性 proteins. AT-2灭活SIV冲击DC对恒河猴病毒血症的长期控制作用 长期感染SIVmac 251的猕猴。此外，我们已经建立了安全和 在健康个体中以及最近在HIV+个体中的DC的免疫原性。基于这些 研究结果，我们将确定用AT-2灭活的HIV脉冲的DC是否诱导治疗性免疫反应， 在慢性感染HIV+个体的队列中的反应。具体目标是：（1）优化 体外人DC捕获、加工和呈递AT-2处理的HIV，作为临床研究的前奏。 研究;（2）开发制备无菌AT-2灭活自体HIV所需的方法， 患者的单核细胞在满足监管要求的水平上，和（3）建立 自体AT-2灭活的HIV致敏的DC在ART抑制的慢性 感染HIV+的队列。这些研究将有助于确定非复制型艾滋病毒，当交付给 DC诱导持久的CD 4和CD 8应答，这有助于控制病毒复制，即使在 艺术的终结

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.