IMMUNIZATION ACTIVATES TRANSIENT SIV VIRAL REPLICATION

免疫激活短暂的 SIV 病毒复制

• 批准号: 8358149
• 负责人: DREW WEISSMAN
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358149
• 关键词: Animals; Anti-Retroviral Agents; Antigens; CD4 Positive T Lymphocytes; Chronic; Contralateral; Cytomegalovirus; Funding; Gagging; Generations; Grant; HIV; HIV Antigens; HIV Infections; Immune; Immunity; Immunization; Individual; Infection; Institution; Macaca; Macaca mulatta; Modeling; National Center for Research Resources; Plasmids; Primates; Principal Investigator; Research; Research Infrastructure; Resources; SIV; Side; Source; T cell response; Therapeutic; Time; United States National Institutes of Health; Viral; cost; cytomegalovirus matrix protein 65kDa; immune activation; lymph nodes; pathogen; peripheral blood; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV infection causes a qualitative and quantitative loss of CD4+ T cell immunity. The institution of anti-retroviral therapy (ART) restores CD4+ T cell responses to many common pathogens, but HIV-specific responses remain deficient. Similarly, therapeutic immunization with HIV antigens of chronically infected ART treated subjects results in poor HIV-specific responses. In this study, we used a macaque model of HIV-infected individuals treated with ART during chronic infection to study the consequences of SIV antigen stimulation in lymph nodes early after immunization. CMV seropositive Mamu A*01 positive rhesus macaques were chronically infected with SIVmac251 and treated with ART. The immune and viral responses to SIV gag and CMV pp65 antigen immunization in draining lymph nodes and peripheral blood was analyzed. Animals were immunized with SIV gag encoding plasmid on one side and CMV pp65 encoding plasmid on the contralateral side, which allowed draining lymph nodes for each antigen to be obtained at the same time from the same animal for direct comparison. We observed that both SIV and CMV antigen immunizations stimulated immune activation and transient antigen-specific T cell responses in inpsilateral lymph nodes. The CMV-specific responses were potent and sustained in the periphery for 50 days post-immunization, while the SIV-specific responses were transient and extinguished quickly. The SIV antigen stimulation induced transient SIV viral replication in the draining lymph nodes. We hypothesize that viral replication in response to SIV antigen stimulation limits the generation of SIV antigen-specific responses, suggesting a mechanism for the early loss and poor HIV-specific CD4+ T cell response observed in HIV-infected individuals.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 HIV 感染会导致 CD4+ T 细胞免疫力的定性和定量丧失。抗逆转录病毒疗法 (ART) 的建立恢复了 CD4+ T 细胞对许多常见病原体的反应，但 HIV 特异性反应仍然不足。同样，对长期感染的 ART 治疗对象使用 HIV 抗原进行治疗性免疫会导致 HIV 特异性反应较差。在这项研究中，我们使用了在慢性感染期间接受 ART 治疗的 HIV 感染者的猕猴模型，以研究免疫后早期 SIV 抗原刺激淋巴结的后果。 CMV 血清阳性 Mamu A*01 阳性恒河猴被 SIVmac251 慢性感染并接受 ART 治疗。分析了引流淋巴结和外周血中对 SIV gag 和 CMV pp65 抗原免疫的免疫和病毒反应。动物在一侧用SIV gag编码质粒免疫，在对侧用CMV pp65编码质粒免疫，这使得可以同时从同一动物获得每种抗原的引流淋巴结以进行直接比较。我们观察到 SIV 和 CMV 抗原免疫刺激了内侧淋巴结中的免疫激活和瞬时抗原特异性 T 细胞反应。 CMV 特异性反应是有效的，并在免疫后 50 天内持续在外周，而 SIV 特异性反应是短暂的并很快消失。 SIV 抗原刺激诱导引流淋巴结中短暂的 SIV 病毒复制。我们假设，响应 SIV 抗原刺激的病毒复制限制了 SIV 抗原特异性反应的产生，这表明在 HIV 感染者中观察到的早期丧失和较差的 HIV 特异性 CD4+ T 细胞反应的机制。