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HIV免疫疗法获重大突破,一览研究进展

2017-04-19 小博 医麦克

近日,关于HIV免疫疗法迎来了两项新突破。来自美国TSRI和中国上海科技大学的研究人员成功构建出抵抗HIV的免疫细胞,有望治愈HIV感染;美国天普大学华人科学家胡文辉等人利用基因编辑技术,从多靶点高效剔除了一种人源化小鼠多个器官组织中的人类HIV病毒。近日,关于HIV免疫疗法迎来了两项新突破:来自美国TSRI和中国上海科技大学的研究人员成功构建出抵抗HIV的免疫细胞,有望治愈HIV感染;美国天

近日,关于HIV免疫疗法迎来了两项新突破。来自美国TSRI和中国上海科技大学的研究人员成功构建出抵抗HIV的免疫细胞,有望治愈HIV感染;美国天普大学华人科学家胡文辉等人利用基因编辑技术,从多靶点高效剔除了一种人源化小鼠多个器官组织中的人类HIV病毒。

近日,关于HIV免疫疗法迎来了两项新突破:来自美国TSRI和中国上海科技大学的研究人员成功构建出抵抗HIV的免疫细胞,有望治愈HIV感染;美国天普大学华人科学家胡文辉等人利用基因编辑技术,从多靶点高效剔除了一种人源化小鼠多个器官组织中的人类HIV病毒。

自艾滋病被发现以来,全球投入了大量的人力物力来开展研究,虽然先后研制出了十几种疫苗和近百种治疗性药物,但迄今尚未发现一种彻底治疗艾滋病的特效药物。作为治疗艾滋病的新武器,“鸡尾酒”疗法一经公布就立刻轰动了整个医学界,世界各国的科学家也给予这种疗法以很高的评价。

现如今,免疫疗法作为癌症的热门疗法炙手可热,又因为病毒感染性疾病相对于肿瘤有着一定的特异性强、突变率可控等特点,所以科学家们也开始利用免疫疗法来治疗HIV感染。

针对艾滋病治疗的相关研究在持续推进,不断取得新的突破。近日,更是迎来两项新突破。那么在治疗艾滋病方面,细胞免疫治疗取得了哪些进展呢?在此小编盘点了近几年HIV免疫疗法的进展,希望与大家共同学习。

强效中和抗体消灭HIV病毒

2015年8月,加州理工学院的科研人员发现了一种特殊的中和抗体。这种抗体能够辨认上述标记蛋白,不管包膜蛋白在艾滋病毒进行感染时变成什么样的构造都无法逃脱这种中和抗体的“法眼”。这种中和抗体的发现为检测并消灭艾滋病患者体内的病毒翻开了新的篇章。

这项研究由生物学教授Pamela Bjorkman领导,相关研究结果发表在《cell》期刊上。

虽然中和抗体能够辨认艾滋病毒表面的包膜刺突,但大多数只能辨认处于闭合态的刺突。另外,每种中和抗体只能辨认刺突上某种特定的目标,或称抗原决定簇。由于通过某些抗原决定簇能够更有效地消灭艾滋病毒,因此,某些中和抗体消灭病毒的能力更强。在2014年,Bjorkman教授和洛克菲勒大学的同事首次在免疫系统还能对抗病毒的艾滋病患者的体内发现了一种叫做8ANC195强效中和抗体。他们发现,这种中和抗体能够通过锚定某种新发现的抗原决定簇来消灭病毒。

他们发现,虽然许多中和抗体能够辨认包膜刺突的闭合态,但是8ANC195更胜一筹,它能够辨认包膜刺突的闭合态以及半开放态。Scharf说:“我们认为,这种抗体能够辨认刺突的两种形态是非常有利的事情。”

另外,由于Scharf等人已经完全掌握8ANC195是如何与病毒刺突结合的完整信息,他们可以开始着手通过基因工程来让它变得更高效、并让它能够辨认更多的艾滋病毒品系。



新型疗法疑似治愈艾滋病患者?

2016年3月,英国的一项HIV治疗临床试验结果表明,在50名接受治疗的患者中,一名44岁男患者其血液测试中未检测到任何的HIV病毒。媒体称,这可能意味着人类第一次清除潜伏在淋巴细胞中的艾滋病毒。

这一结果十分令人高兴,但说到HIV的治愈还为时尚早。帝国理工大学Sarah Fidler教授表示:“实验中采用的新疗法旨在清除包括潜伏的艾滋病毒在内的体内所有艾滋病毒。目前已在临床实验上取得巨大进展,但离临床用于根治癌症还有很长的路要走。”

该研究选择感染艾滋病毒六个月内的患者进行临床试验,使用了“Kick and Kill”疗法:Kick的部分依靠Vorinostat药物来“踢活”被感染的休眠T细胞,同时用两种疫苗使免疫系统能够识别这些被激活的细胞,从而完成Kill这一步。这项技术被誉为“最有可能根治艾滋病的疗法之一”。

面对众多媒体“艾滋病患者疑似被治愈” 的报道,RIVERS项目研究人员在网站上发表了官方声明:“我们将于2018年得到最终研究成果。在此之前,不能断言治疗是否真的有效。但从目前病人的状态,我们得知人体对这种疗法耐受,这为后续研究提供可能。我们期待最终获得突破性成果,但在那之前,我们并不能得出艾滋病已被治愈的结论。”



首次利用CAR-T免疫疗法杀死被HIV感染的细胞

2016年8月,一项新的研究发表在《Virology》期刊上,来自美国加州大学洛杉矶分校AIDS研究所和AIDS研究中心的研究人员证实最近发现的抗体能够被用来作为CAR的头部,利用CARs构建强有力的免疫响应,然后就能够利用这种CAR-T杀死被HIV-1感染的细胞。

CAR-T是对T细胞进行基因改造使得在它们的表面上产生靶向和杀死含有病毒或肿瘤蛋白的特异性细胞的受体而制造出来的。嵌合受体成为正在进行的研究基因免疫疗法如何能够被用来抵抗癌症的焦点。但是,加州大学洛杉矶分校大卫-格芬医学院传染病系医学教授Otto Yang博士说,它们也能够被用来产生强大的抵抗HIV的免疫反应。

尽管人体的免疫系统起初确实对HIV作出反应并攻击它,但是这种对HIV的完全攻击由于这种病毒能够潜藏在不同的T细胞中和快速地复制而最终丧失殆尽,并对免疫系统造成破坏,从而让人体容易遭受一系列感染和疾病。科学家们一直在寻找增强免疫系统抵抗HIV的方法,如今,它似乎表明CAR-T就是被用来抵抗HIV的武器。

研究人员获得新一代的抗体,将它们改造为人工T细胞受体,从而对杀伤性T细胞进行重编程而能够杀死被HIV感染的细胞。其他人已使用抗癌症抗原的抗体来制造抵抗癌症的人工T细胞受体,并且证实这有助于癌症治疗。加州大学洛杉矶分校是首次设计这种抵抗HIV的策略。

在这项新的研究中,研究人员使用了7种最近发现的“广泛中和抗体”,这些广泛中和抗体能够结合多种入侵的HIV毒株,而不是较早前分离出的往往只结合少数HIV毒株的抗体。这些广泛中和抗体被改造为具有抵抗广泛的HIV毒株的人工CAR-T细胞受体。在实验室测试中,研究人员发现所有的这种广泛中和抗体能够不同程度地指导杀伤性T细胞增殖、杀死被HIV感染的细胞和抑制被感染的细胞中的病毒复制。

这种免疫疗法有巨大的希望在进一步的研究中向前进一步推进。



疫苗联合免疫兴奋剂有望长期抑制HIV

2016年10月,一项由贝斯以色列女执事医疗中心的研究人员(BIDMC)与沃尔特里德陆军研究所科学家的合作研究(WRAIR)已经证明了一种实验性疫苗联合一种先天免疫兴奋剂有助于艾滋病毒携带者病毒的缓解。在动物试验中,该联合方法降低了外周血和淋巴结中的病毒DNA水平,促进了病毒抑制并延迟了抗逆转录病毒疗法(ART)停药后的病毒反弹。相关研究结果发表在《Nature》上。

通常情况下, 疫苗会“教”机体通过引发免疫反应而清除病毒入侵者。然而,HIV病毒攻击免疫系统的细胞。病毒杀死了大多数受感染的免疫细胞,而其他的进入休眠状态。这种处于休眠状态的被感染细胞(研究人员认为抗逆转录病毒治疗期间艾滋病病毒仍然隐藏在这些休眠细胞内)是艾滋病目前无法治愈的主要原因。Barouch和他的同事们正在研究策略来找出这些隐藏的病毒,目的是从体内消除它。

在为期两年的长期研究中,研究人员检测了36个感染猴免疫缺陷病毒(SIV)(类似艾滋病毒的病毒,感染非人类的灵长类动物)的恒河猴的病毒载量。在使用抑制ART药物6个月之后,

发现Ad26 / MVA疫苗接种与TLR7刺激的联合被证明比单独一种治疗更有效。

为了评估疫苗和免疫兴奋剂的功效,研究人员对所有动物停止ART并继续监测它们的病毒载量。只接受疫苗的动物证明由病毒载量的一些降低, 但与对照组相比,接受疫苗/免疫兴奋剂联合治疗的动物表现出血浆病毒RNA水平的降低以及2.5倍的病毒反弹延迟。所有九个动物显示出病毒载量的降低,三分之一的动物体内检测不到病毒。

Barouch说:“这绝对是我们可以工作的基础。”

注射抗体取缔服用药物?新型HIV免疫疗法有望被开发

2016年11月,《New England Journal of Medicine》期刊发表一篇文章揭示了免疫治疗在艾滋病领域的最新突破。来自于宾夕法尼亚大学Perelman医学院、阿拉巴马大学和美国国家卫生研究院(NIH)的科学家们发现,注射一种广泛性中和抗体(bNAb),能够有效抑制病毒,且适度延迟HIV潜伏病毒“反弹”的时间。

研究团队筛选了一种广泛性中和抗体VRC01,通过注射发现它可以在患者体内高表达,从而控制病毒“反弹”。虽然目前的研究结果表明,这种抑制能力不超过8周。但是它预示着,HIV特异性抗体能够长效抑制甚至消灭HIV病毒,有望取缔患者对抗逆转录病毒药物(ART)的依赖,从而迈出长效抑制病毒的重要一步。

在艾滋病药物研发初期,服用单个抗逆转录病毒药物会引发快速耐药性和病毒反弹等问题。伴随着鸡尾酒等治疗策略的推出,复合型药物能够从不同角度对抗病毒,从而增强了病毒抑制的时效性。

目前,大多数艾滋病患者每日仅需服用一次复合型ART药物,它可以延长患者寿命,并提升整体健康指标。但是,ART药物不能根除潜伏的HIV,坚持每日服用抗逆转录病毒药物对于很多患者,特别是医疗水平有限的地区,依然是个问题。一旦停止用药,绝大多数艾滋病患者体内的病毒都会重新崛起,加重患者病情。

现在,免疫疗法或可成为第二选择。研究人员通过比对患者参与试验之前的血液样本,发现抗体免疫治疗可以短时间内抑制HIV病毒。宾夕法尼亚大学艾滋病临床试验中心Pablo Tebas表示,目前研究团队关注的是一个抗体,他们认为可以筛选出更强大的抗体组合,以便更有效地控制病毒。

抗体连接细胞群,使HIV无处可逃

2017年4月,在一项新的研究中,来自美国斯克里普斯研究所(TSRI)和中国上海科技大学的研究人员开发一种方法将抵抗人类免疫缺陷病毒(HIV)的抗体附着到免疫细胞表面上,从而产生抵抗HIV的细胞群体。在实验室条件下,他们的实验证实这些抵抗性细胞能够快速地替换被HIV感染的免疫细胞,从而有助潜在地治愈HIV感染者。

在之前的疗法中,抗HIV抗体在血液中以相对较低水平地自由游动。然而,在TSRI开发的这种新技术中,抗HIV抗体附着到免疫细胞的表面上,阻断HIV结合一种至关重要的细胞受体,从而阻止扩散HIV感染。研究人员将其称之为“邻近效应(neighbor effect)”。将抗HIV抗体附着到免疫细胞表面上要比很多抗HIV抗体在整个血液中流动更加有效。

研究人员测试了该技术是否能够抵抗HIV。为了感染人,所有的HIV毒株需要结合一种被称作CD4的细胞表面受体。因此,他们选择了能够潜在地保护正常情形下被HIV杀死的免疫细胞表面上的这种受体的抗体,然后对这些抗体进行测试。他们对免疫细胞进行基因改造,使之在细胞表面上表达能够结合CD4的抗体。在将这些基因改造的免疫细胞与HIV一起孵育后,他们最终获得抵抗HIV的免疫细胞群体。这些抗体识别CD4结合位点,从而阻断HIV结合这种受体。

这些研究人员进一步证实,相比于自由游动的可溶性抗体,这些测试的附着到免疫细胞表面上的抗体更加有效地阻断HIV感染。



CRISPR技术成功剔除小鼠HIV病毒

2017年4月,美国《Molecular Therapy》杂志近日刊登了美国天普大学华人科学家胡文辉等人的最新研究成果:他们利用基因编辑技术,从多靶点高效剔除了一种人源化小鼠多个器官组织中的人类HIV病毒。

胡文辉和同校同事卡迈勒·哈利利以及匹兹堡大学杨文彬等人首先利用HIV病毒感染人源化BLT小鼠,然后借助腺相关病毒(AAV)作为载体,把有“基因剪刀”之称的CRISPR/Cas9基因编辑工具运送到潜伏感染小鼠体内。2到4周后,他们在多个小鼠器官组织中检测到艾滋病病毒基因组被切除。

众所周知,HIV病毒基因具有“善变性”,胡文辉团队这次提出了一种新思路,用多靶点基因编辑取代单靶点,以遏制病毒逃逸。他们针对艾滋病病毒转录区和结构区设计了4个向导RNA(核糖核酸),引导Cas9酶到预定位置实现多靶点切除,显着增加了艾滋病病毒的剔除效率。运用“基因魔剪”剔除艾滋病病毒还有一大优点:不影响靶细胞的存活和功能,即“只杀病毒不杀细胞”。

虽然目前基因编辑疗法尚不能100%清除动物体内的艾滋病病毒,但能够显着降低潜伏病毒量,因此与抗逆转录病毒药物组合使用不失为一种有希望的艾滋病治疗策略。

原始出处:

Scharf L, Wang H, Gao H, Chen S,et al. Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env. Cell. 2015 Sep 10.

Ali A, Kitchen SG, Chen IS, Ng HL, et al. HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies. J Virol. 2016 Jul 11.

Yin C, Zhang T, Qu X, Zhang Y, et al. In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-Guide RNAs in Animal Models. Mol Ther. 2017 Mar 30.

Bar KJ, Sneller MC, Harrison LJ, Justement JS, et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N Engl J Med. 2016 Nov 24.

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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-05-05 1e1b8c04m38(暂无匿称)

    学习

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=194066, encodeId=970419406616, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri May 05 09:19:24 CST 2017, time=2017-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=193630, encodeId=1ab5193630a6, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=150, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu May 04 09:17:46 CST 2017, time=2017-05-04, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-05-04 1e1b8c04m38(暂无匿称)

    学习

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=194066, encodeId=970419406616, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri May 05 09:19:24 CST 2017, time=2017-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=193630, encodeId=1ab5193630a6, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=150, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu May 04 09:17:46 CST 2017, time=2017-05-04, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-05-03 1e1b8c04m38(暂无匿称)

    学习

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=194066, encodeId=970419406616, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri May 05 09:19:24 CST 2017, time=2017-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=193630, encodeId=1ab5193630a6, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=150, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu May 04 09:17:46 CST 2017, time=2017-05-04, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-05-02 1e1b8c04m38(暂无匿称)

    学习

    0

  5. 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GetPortalCommentsPageByObjectIdResponse(id=192568, encodeId=d72e19256825, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=178, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Mon May 01 17:14:15 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192196, encodeId=b634192196ea, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sun Apr 30 13:58:53 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-05-01 1e1b8c04m38(暂无匿称)

    学习

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=194066, encodeId=970419406616, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri May 05 09:19:24 CST 2017, time=2017-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=193630, encodeId=1ab5193630a6, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=150, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu May 04 09:17:46 CST 2017, time=2017-05-04, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-04-30 1e1b8c04m38(暂无匿称)

    学习

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=194066, encodeId=970419406616, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri May 05 09:19:24 CST 2017, time=2017-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=193630, encodeId=1ab5193630a6, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=150, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu May 04 09:17:46 CST 2017, time=2017-05-04, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191193, encodeId=0f3d19119332, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=118, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu Apr 27 20:51:49 CST 2017, time=2017-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380781, encodeId=64ee1380e81d1, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=109, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8e886, createdName=仁者大医, createdTime=Thu Apr 20 23:13:00 CST 2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-04-29 1e1b8c04m38(暂无匿称)

    学习

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=194066, encodeId=970419406616, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri May 05 09:19:24 CST 2017, time=2017-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=193630, encodeId=1ab5193630a6, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=150, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Thu May 04 09:17:46 CST 2017, time=2017-05-04, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=191890, encodeId=194c1918904e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Sat Apr 29 18:24:59 CST 2017, time=2017-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191447, encodeId=9db819144e6e, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20161217/IMG585499DFC35A96490.jpg, createdBy=72381996390, createdName=1e1b8c04m38(暂无匿称), createdTime=Fri Apr 28 11:12:24 CST 2017, time=2017-04-28, status=1, ipAttribution=), 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2017, time=2017-04-20, status=1, ipAttribution=)]
    2017-04-28 1e1b8c04m38(暂无匿称)

    学习

    0

  9. 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    2017-04-27 1e1b8c04m38(暂无匿称)

    学习

    0

  10. 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