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题名	SHIV89.6感染中国猕猴的免疫活化和功能变化及CD24-Fc对SIVmac239感染中国猕猴免疫重建的作用研究
作者	田仁荣
学位类别	博士
答辩日期	2015-05
授予单位	中国科学院研究生院
授予地点	北京
导师	郑永唐
关键词	慢性免疫活化 HIV-1 免疫重建 SIVmac239 cART SHIV89.6 CD24-Fc 中国猕猴 艾滋病
其他题名	Alterations of T cell immune activation and function in SHIV89.6-infected Chinese rhesus macaques and the effects of CD24-Fc on SIVmac239-infected Chinese rhesus macaque
学位专业	细胞生物学
中文摘要	AIDS/HIV-1是危害公众健康的重大传染病之一。目前cART是AIDS/HIV-1防治的主要手段。虽然长期的cART能有效抑制病毒复制，部分促进免疫重建，其成功的开展促使使HIV-1的感染由致死性疾病变成慢性疾病，但是cART 存在不能完全实现免疫重建，部分免疫重建也需要数年，药物的长期毒副以及免疫重建综合症等问题。目前研究表明cART对免疫重建的效果与进行cART前免疫损伤严重程度有关。在血浆病毒受到抑制时，免疫重建的效果受组织中低水平的病毒复制以及慢性活化的影响。目前伴随HIV-1的致病机制的逐渐解析，免疫学、细胞生物学以及基因工程技术的迅 速发展，多种免疫治疗和细胞治疗以及基因治疗已在动物水平以及临床水平开展了尝试，虽然这些策略大多处于探索阶段，但是它们为AIDS/HIV-1治愈或功能性治愈带来了曙光。 慢性免疫活化是致病性免疫反应，其包含多个细胞和分子进程，在致病性HIV-1/SIV感染中，其加速CD4+ T细胞丢失、促进免疫衰老、破坏免疫系统的再生能力、破坏免疫组织的结构进而影响细胞的自我平衡，慢性免疫活化还促进了慢性炎症形成，增加HIV-1感染并发症和死亡的的风险。慢性免疫活化是致病性HIV-1/SIV感染的特征，也是HIV-1致病的机制之一，其与AIDS疾病进程相关。HIV-1/SIV感染导致的天然以及适应性免疫活化、病毒蛋白的直接作用、微生物移位作用、临床感染或隐性共感染作用、IFN-α和炎症介质的作用以及免疫调节反应的失衡等多种因素与慢性免疫活化相关。目前除cART外，免疫抑制剂、抗炎症药物、他汀类药物、抗共感染药物以及微生物移位的治疗等方法已进入临床病人的治疗试验，并显示出初步的疗效。 AIDS非人灵长类动物模型是研究HIV-1致病机制以及AIDS/HIV-1防治策略的重要工具。多种SIV毒株以及基因工程改造的嵌合病毒SHIV已用于感染如猕猴、平顶猴以及食蟹猴等非人灵长类，以便研究HIV-1的致病机制，传播机制以及防治策略。中国猕猴被SIV感染后其病毒学和免疫学参数的变化，导致免疫损伤以及发病速率等与HIV-1感染人相似，它在HIV-1研究中的作用优于印度猕猴。SHIV89.6是减毒的嵌合病毒，其感染后对组织的损伤有限，对免疫学指标的研究较少，经过二轮体内传代获得的子代病毒SHIV89.6P具有很强致病性。目前SHIV89.6的致病性还不清楚。本研究发现SHIV89.6感染后127周内，42.86%的感染动物死亡。通过对正常猴、SHIV89.6感染后127周仍存活以及127周内死亡等三组动物免疫学参数的对比研究，我们发现SHIV89.6感染后病毒复制水平不高，对T细胞的动力学影响较小，但是感染后死亡组动物在死亡前免疫活化水平显著升高、IFN-α表达水平显著降低，T细胞功能发生多项异常，同时免疫活化标志的表达水平、IFN-α的表达水平以及T细胞的功能存在多种相关，我们的研究结果揭示高水平的免疫活化以及细胞因子表达的异常可能导致了SHIV89.6感染的猕猴的死亡。 本研究对免疫活化作为HIV-1治疗干扰靶标提供依据，同时提示免疫活化以及细胞因子表达谱能够作为治疗效果以及预后的指标。 免疫治疗是AIDS/HIV-1治疗的重要发展方向，抑制炎症反应以期抑制免疫活化是免疫治疗的重要途径。CD24-Fc能够选择性抑制DAMP导致的炎症反应，而HIV-1感染也能导致DAMP和炎症水平升高。本研究我们采用SIVmac239感染的动物模型，研究CD24-Fc在HIV-1/SIV感染中的作用，并探讨通过抑制炎症反应治疗艾滋病免疫病理损伤的治疗策略。我们的研究结果显示，CD24-Fc的安全性较高、耐受性较好，其对感染动物具有保护作用，表现为延缓体重的降低，提高感染动物的存活率。对其作用机制研究发现CD24-Fc不影响CD4+ T细胞数，但是其能延缓病毒载量上升，通过抑制HLA-DR表达抑制CD8+ T细胞活化，CD24-Fc有利于na?ve CD8+ T 比率、CD4+ T以及CD8+ T细胞功能能亚群的维持，有利于直肠和回肠Th17/Treg比率的维持，CD24-Fc处理还能使产生IL-21的T细胞比率提高，使Treg细胞比率降低，同时CD24-Fc处理对直肠中炎症因子以及ISGS的表达还具有抑制作用。我们的研究结果提示CD24-Fc治疗是一种安全有效的治疗方法，其在HIV-1治疗中具有临床应用的潜力。
英文摘要	AIDS/HIV-1 is one of infectious diseases which most seriously threaten public health. Now, cART is the main strategy against HIV-1 infection. Although long term cART can suppress plasma virus load to under-detected level, but there are also many other problems, such as incomplete immune reconstitution, HIV-1 reservior, drug resistance mutants, side effects of drug and immune reconstitution inflammatory syndrome. Immune reconstitution has been reported to be associated with degree of damage before cART. But immune damage can not be reversed by cART at early stage of infection. Now chronic immune activation induced by low level replication in tissue whereas plasma virus load was suppressed by cART is commonly believed to be associated with failure of immune reconstitution. Recently, accompanying with the development of immunology, cell Biology，molecular and gene engineering, the pathogenesis of HIV-1 has been profoundly elucidated and many other strategies, such as immunotherapy, cell therapy and gene therapy have been developed to cure HIV-1 infected patients. Some of them have been reported with excellent effects. Chronic immune activation is a pathogenic immune response which including many complex cellular and molecular process. In pathogenic HIV-1/SIV infection, it not only can promote process to AIDS through driving loss of CD4+ T cell, accelerating immune consenescence and destroying regeneration of immune system and destructing the architecture of lymphoid tissue, it also forms chronic inflammation environment which increases incidence of complication and mortality in HIV-1 infected patients. Chronic immune activation is not only a character of pathogenic HIV-1/SIV infection, but also mechanism of HIV-1/SIV pathogenicities. Many factors have been reported associated with chronic immune activation, such as activation of innate immune and adoptive immune, stimulation of viral proteins, immune response to opportunistic infection, IFN-α and inflammatory cytokines, microbial translocation and imbalance of immune regulation. Now, there are many drugs beening used to restrain immune activation and most of them belong to immunosuppressant, anti-inflammation drugs, statins, anti-coinfection drugs and inhibitor of microbial translocation. Chinese rhesus macaque (CRM) is an ideal experimental animal for HIV/SIV pathogenesis and vaccine research. SHIV89.6 has been reported as an attenuated virus because most of time SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, the SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability SHIV89.6 is not well elucidated. In this research, we found that 6 of 14 SHIV89.6-infected CRMs died during 127 weeks after infection. Then we found there were especially high immune activation, low IFN-α expression and distinctive cytokine expression profiles in the infected and dead group (ID) monkeys, while there were only few changes of CD4+ T counts and distribution of T cell subsets in ID group monkeys. Also, there was a similar dynamic of viral load between infected and survival group (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-α expression and frequencies of cytokine secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential to CRM and high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected CRM. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be excellent guidelines for disease progression and marks for therapy. Immune therapy is an important component of AIDS/HIV-1 therapy. It has been suggested that restrain immune activation through modulating inflammatory response can be an ideal approach for immune therapy. Through interacting with siglec G, CD24-Fc can selectively repress inflammatory response stimulated by DAMP. Given that elevated DAMP and inflammatory mediators in HIV-1 infection patients, we speculate that CD24-Fc maybe be benefit for HIV-1 patients. In our study, we evaluated effects of CD24-Fc in SIVmac239 infected CRMs. It was shown that CD24-Fc is safe and tolerance for SIVmac239 infected-CRMs. CD24-Fc administration can provide protection to infected animals, showing delaying loss of weight and increasing survival. Although CD24-Fc can’t promote recovery of CD4+ T cell counts, but it can delay increasing of virus load and reduce CD8+ T cell activation (% HLA-DR+CD38+T) through downregulating expression of HLA-DR. CD24-Fc also can maintain frequencies of na?ve CD8+ T cell and regulate T cell functional subsets, including maintaining frequencies of IL-2 and TNF-alpha secreting CD4+ T cell and CD8+ T cell in PBMC and tissue, increasing frequencies of IL-21 secreting CD4+ T and CD8+ T cell and decreasing frequencies of Treg independent of IDO and TGF-beta. Except that, CD24-Fc can selectively inhibit expression of inflammatory factors and ISGs in rectum lymphocyte. Briefly, our results suggest that CD24-Fc administration is a safe and effective approach for AIDS/HIV-1 therapy, and it may have potential to clinic use.
语种	中文
内容类型	学位论文
源URL	[http://159.226.149.26:8080/handle/152453/10183]
专题	昆明动物研究所_分子免疫药理学
推荐引用方式 GB/T 7714	田仁荣. SHIV89.6感染中国猕猴的免疫活化和功能变化及CD24-Fc对SIVmac239感染中国猕猴免疫重建的作用研究[D]. 北京. 中国科学院研究生院. 2015.

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