Insensitivity of paediatric HIV-1 subtype C viruses to broadly neutralising monoclonal antibodies raised against subtype B.
Insensitivity of paediatric HIV-1 subtype C viruses to broadly neutralising monoclonal antibodies raised against subtype B.
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DOI：
10.1371/journal.pmed.0030255
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发表时间：
2006-07
期刊：
影响因子：
15.8
通讯作者：
Morris L
中科院分区：
文献类型：
--
作者：
Gray ES;Meyers T;Gray G;Montefiori DC;Morris L
在南非，已经提出了一项I期临床试验，该试验使用中和单克隆抗体（mab）作为被动免疫预防来预防HIV-1的母婴传播。为了评估这种方法的适用性，我们测定了儿童HIV-1亚型C病毒对广泛中和的单克隆抗体igg1212、2G12、2F5和4E10的敏感性。从7名感染HIV-1亚型C的儿童中克隆了gp160包膜基因，并用于构建env假型病毒，并在单周期中和试验中进行了测试。通过包膜基因的序列分析确定了其中三个单克隆抗体的表位。7种HIV-1亚型C假病毒体对2G12或2F5均不敏感，这与定义2G12表位的关键n -链聚糖的缺失以及2F5表位的残基替换有关。4种病毒对igg1112敏感，7种病毒均对4E10敏感。只有4E10单克隆抗体对HIV-1亚型C株具有显著活性，而2G12和2F5单克隆抗体无效，igg1112部分有效。因此，建议在南部非洲和其他HIV-1亚型C病毒占主导地位的地区，不要将2G12和2F5单克隆抗体用于被动免疫实验。艾滋病是由艾滋病毒引起的。通过杀死人体免疫系统的细胞，HIV感染使人们容易受到许多潜在致命的细菌和病毒疾病的攻击。艾滋病毒最常见的传播途径是与受感染的伴侣发生无保护的性行为，但它也可以在怀孕后期或分娩时由母亲传染给孩子，也可以通过母乳传播。如果不及时治疗，至少四分之一的受感染妇女将把艾滋病毒传染给她们的婴儿。但是，如果受感染的妇女在怀孕后期接受抗艾滋病毒的药物治疗，即所谓的抗逆转录病毒药物，如果不进行母乳喂养，那么每100个婴儿中只有一到两个会感染艾滋病毒。此外，选择性剖腹产已被发现对艾滋病毒感染有保护作用。这一做法的实施大大减少了发达国家的母婴传播，但大多数感染艾滋病毒的妇女生活在获得抗逆转录病毒药物的机会有限的发展中国家。在这些情况下，使用单剂量一种抗逆转录病毒药物治疗孕妇（怀孕和分娩期间）及其新生儿，可将艾滋病毒传播减半，尽管世卫组织/联合国艾滋病规划署建议在资源贫乏环境中采用简单的产前、产时和产后抗逆转录病毒治疗方案，以实现低于5%的传播水平。这些策略不会对母乳传播产生影响，在这些环境中，母乳传播占传播的一半。减少母乳传播艾滋病毒的一种方法可能是“被动免疫”。在这种方法中，新生儿将被注射HIV特异性抗体——一种附着在HIV表面分子上的蛋白质。因为病毒利用这些分子侵入婴儿的免疫细胞，注射的抗体可能会阻止母亲的艾滋病毒在她的后代身上扎根。在实验室中已经制造出四种抗体——所谓的人类单克隆抗体——它们与主要在欧洲和北美发现的HIV亚型B的表面结合，阻止HIV杀死人类细胞。然而，在非洲分离的大多数艾滋病毒是C亚型，因此在这项研究中，研究人员测试了这些抗体是否能阻止在实验室中生长的艾滋病毒C亚型杀伤细胞。他们认为，在婴儿身上测试被动免疫之前，抗体应该在体外发挥作用，这一点很重要。研究人员从南非约翰内斯堡出生的婴儿身上分离出几种亚型C病毒，并从中制造出人工病毒（称为“伪型”病毒）。然后，这些人造病毒可以在实验室测试中用于观察人类单克隆抗体是否可以防止病毒感染人类细胞，也就是说，病毒是否对抗体“敏感”。所有的病毒都对其中两种抗体（2G12和2F5）不敏感，研究人员表明，这是因为病毒缺乏这些抗体识别的HIV表面分子的特定部分。其中四种病毒对一种名为igg1112的抗体敏感，所有病毒都对抗体4E10敏感，尽管高浓度的病毒在人体内可能难以达到。最后，研究人员报告说，同时使用所有四种抗体并没有提高病毒的敏感性。鉴于这些结果，研究人员警告说，在大多数人感染HIV亚型C病毒的地区，不要使用2G12和2F5抗体进行被动免疫，以防止母婴传播，特别是产后传播。此外，由于动物研究表明，在实验室测试中，只有至少三种具有抗HIV活性的单克隆抗体的组合才能提供对HIV感染的完全保护，研究人员质疑是否应该用现有的抗体开始任何关于被动免疫的临床试验。由于观察到4E10和2F5会对人体细胞上的抗原产生反应，这可能会使它们在人体中使用不安全，但迄今为止，在接受这些抗体治疗的成年人中没有发现不良反应，因此他们对此类试验的怀疑更加强烈。然而，这些实验使用的是基于实验室的人工分析，这些抗体可能会更有效地杀死人类的艾滋病毒C亚型；免疫系统的其他成分可能会帮助他们对付病毒。如果这些抗体的临床研究继续进行，必须对这些试验中的婴儿进行仔细监测，以确保抗体是安全的，他们和他们的母亲也应该根据世卫组织/联合国艾滋病规划署的指导方针获得最佳的抗逆转录病毒预防药物。在一篇相关的PLoS Medicine Perspective论文（http://dx.doi.org/10.1371/journal.pmed.0030259）中，Miroslaw Gorny1和Susan Zolla-Pazner进一步讨论了这项研究，并强调迫切需要确定这种抗体的被动免疫是否可以减少艾滋病毒的母婴传播，如果可以的话，最好的抗体是什么。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0030255访问这些网站。•国家过敏和传染病研究所关于艾滋病毒感染和艾滋病的情况介绍•美国卫生和人类服务部关于艾滋病毒/艾滋病的信息，包括预防母婴传播的临床准则和情况介绍•美国疾病控制和预防中心关于艾滋病毒/艾滋病的信息；包括关于预防母婴传播的页面•MedlinePlus百科全书中关于艾滋病毒/艾滋病的条目•预防艾滋病毒母婴传播Web页面对7名感染艾滋病毒1亚型C的儿童的病毒进行的评估显示，对四种单克隆抗体的敏感性普遍较差，这些抗体被提议用于被动免疫预防试验，以防止母婴传播。
A Phase I clinical trial has been proposed that uses neutralising monoclonal antibodies (MAbs) as passive immunoprophylaxis to prevent mother-to-child transmission of HIV-1 in South Africa. To assess the suitability of such an approach, we determined the sensitivity of paediatric HIV-1 subtype C viruses to the broadly neutralising MAbs IgG1b12, 2G12, 2F5, and 4E10. The gp160 envelope genes from seven children with HIV-1 subtype C infection were cloned and used to construct Env-pseudotyped viruses that were tested in a single-cycle neutralisation assay. The epitopes defining three of these MAbs were determined from sequence analysis of the envelope genes. None of the seven HIV-1 subtype C pseudovirions was sensitive to 2G12 or 2F5, which correlated with the absence of crucial N-linked glycans that define the 2G12 epitope and substitutions of residues integral to the 2F5 epitope. Four viruses were sensitive to IgG1b12, and all seven viruses were sensitive to 4E10. Only 4E10 showed significant activity against HIV-1 subtype C isolates, while 2G12 and 2F5 MAbs were ineffective and IgG1b12 was partly effective. It is therefore recommended that 2G12 and 2F5 MAbs not be used for passive immunization experiments in southern Africa and other regions where HIV-1 subtype C viruses predominate. AIDS is caused by HIV. By killing the cells of the body's immune system, HIV infection makes people vulnerable to many potentially fatal bacterial and viral diseases. HIV is most commonly spread through unprotected sex with an infected partner but it can also pass from mother to child during late pregnancy or birth, or through breast milk. At least one in four infected women will transmit HIV to their babies if left untreated. But if infected women are treated with drugs that fight HIV—so-called antiretrovirals—during late pregnancy and if breastfeeding does not occur, only one to two babies in 100 will become infected with HIV. In addition, elective Caesarian section has been found to be protective against HIV infection. Implementation of this approach has greatly reduced mother-to-child transmission in developed countries, but most HIV-infected women live in developing countries where access to antiretrovirals is limited. In these cases, treatment of pregnant women (during pregnancy and delivery) and their newborn babies with a single dose of one antiretroviral drug, which can halve HIV transmission, is used, even though WHO/UNAIDS recommends simple antenatal, intrapartum, and postnatal antiretroviral regimens to achieve levels of less than 5% transmission in resource poor settings. These strategies will not have an impact on breastmilk transmission, which accounts for half the transmissions in these settings. One way to reduce breastmilk transmission of HIV might be by “passive immunization.” In this, newborn babies would be injected with HIV-specific antibodies—proteins that stick to molecules on the surface of HIV. Because the virus uses these molecules to invade the baby's immune cells, injected antibodies might stop HIV from the mother becoming established in her offspring. Four antibodies have been made in the laboratory—so-called human monoclonal antibodies—that bind to the surface of HIV subtype B, which is found mainly in Europe and North America, and stop HIV from killing human cells. However, most HIV isolated in Africa is subtype C, so in this study researchers have tested whether these antibodies prevent HIV subtype C killing cells grown in the laboratory. It is important, they argue, that antibodies should be shown to work outside the body before testing passive immunization in babies. The researchers isolated several subtype C viruses from babies born in Johannesburg, South Africa, and made artificial viruses (known as “pseudotyped” viruses) from them. These artificial viruses could then be used in tests to see whether the human monoclonal antibodies could prevent the viruses infecting human cells in a laboratory test, that is, whether the viruses were “sensitive” to the antibodies. All the viruses were insensitive to two of the antibodies (2G12 and 2F5), and the researchers show that this was because the viruses lacked the specific parts of the HIV surface molecules recognized by these antibodies. Four of the viruses were sensitive to an antibody called IgG1b12, and all were sensitive to antibody 4E10, albeit at high concentrations that might be difficult to achieve in people. Finally, the researchers report that the sensitivity of the viruses was not enhanced by using all four antibodies at the same time. Given these results, the researchers warn against using 2G12 and 2F5 antibodies for passive immunization to prevent mother-to-child transmission, in particular postnatal transmission, in areas where most people are infected with HIV subtype C viruses. Furthermore, because animal studies have indicated that only combinations of at least three monoclonal antibodies with activity against HIV in laboratory tests provide complete protection against HIV infection, the researchers question whether any clinical trials on passive immunization should be started with currently available antibodies. Their doubts about such trials are heightened by observations that 4E10 and 2F5 react against antigens present on human cells, which might make them unsafe for use in people, although so far no adverse effects have been seen in adults treated with these antibodies. However, these experiments used an artificial laboratory-based assay and it's possible that these antibodies might kill HIV subtype C more effectively in people; other components of the immune system might help them deal with the virus. If clinical studies of these antibodies do go ahead, it is essential that the babies in these trials must be carefully monitored to ensure that the antibodies are safe, and they and their mothers should also be given access to optimal antiretroviral prophylaxis according to WHO/UNAIDS guidelines. In a related PLoS Medicine Perspective paper (http://dx.doi.org/10.1371/journal.pmed.0030259), Miroslaw Gorny1 and Susan Zolla-Pazner discuss the study further and stress the critical need to determine if passive immunization with such antibodies could decrease mother-to-child transmission of HIV, and if so what the best antibodies would be. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030255. • National Institute of Allergy and Infectious Diseases fact sheets on HIV infection and AIDS • US Department of Health and Human Services information on HIV/AIDS, including clinical guidelines and fact sheets on preventing transmission from mother to child • US Centers for Disease Control and Prevention information on HIV/AIDS, including pages on the prevention of mother-to-child transmission • MedlinePlus encyclopedia entry on HIV/AIDS • Preventing mother-to-child transmission of HIV Web page Assessment of viruses from seven children with HIV-1 subtype C infection showed generally poor sensitivity to four monoclonal antibodies proposed for a trial of passive immunoprophylaxis to prevent mother-to-child transmission.