HIV感染早期阻断新途径

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New Approach Stops HIV At Earliest Stage Of Infection

ScienceDaily (Feb. 28, 2008) — Researchers at The Scripps Research Institute have developed a new two-punch strategy against HIV and they have already successfully tested aspects of it in the laboratory.

Their study, which appears in the online Early Edition of the Proceedings of the National Academy of Sciences, may re-energize attempts to create a preventive/therapeutic vaccine against HIV, say the authors. To date, more than a dozen candidate vaccines, which have attempted to raise immunity against the spiky proteins on the viral envelope, have all failed in clinical testing.

The investigators have created devices they call glycodendrons that are designed to do two things at once: inhibit the transport of HIV from where it traditionally enters the body, preventing it from moving deeper inside where it can infect immune cells; and set up an immune antibody response to a unique carbohydrate structure on the surface of the virus.

\"This paper is about a new direction in HIV vaccine design,\" said the study's lead investigator, Scripps Research Chemistry Professor Chi-Huey Wong. \"Results we have so far are very promising.\"

To date, he says the devices have been able to stimulate the immune system of mice to induce antibodies against HIV surface glycoprotein, and, in laboratory studies, have been able to block the virus from infecting immune cells.

Targeting One Multi-Purpose Area on HIV

This new approach capitalizes on two recent findings in the field of HIV research. One is the discovery that HIV takes a Trojan horse approach to reach cells it needs to infect deep inside the human body. Scientists have described how, when the virus enters the body through sexual contact, it hitches a ride with the dendritic cells of the immune system that stand guard for invaders at the mucosal lining of tissues.

The virus outsmarts these cells, however, and latches onto a particular receptor protein, known as DC-SIGN, on the dendritic cells. By sticking to these immune system fighters, HIV manages to evades immune detection while the dendritic cells travel to the ultimate goal of the virus: immune T-Cells in the lymphoid system, which HIV then invades, setting up a deadly infection that spreads.

The second discovery is that an antibody exists that can signal immune destruction of the virus. The antibody, 2G12, protects people who have it against HIV progression, but very few of those who are infected put up such an immune reaction, said the study's first author, Sheng-Kai Wang, a graduate student in Wong's laboratory. Scientists at Scripps Research have defined the details of the action of the antibody and found that recognizes a dense cluster if sugars on one region of the virus's spiky protein coating--which is, strikingly, the same area that HIV uses to bind to the DC-SIGN protein on dendritic cells.

Earlier, Scripps Research Professor Dennis Burton, a co-author of this study, and Wong designed and tested synthetic constructs to mimic the clusters of sugars recognized by 2G12 that could form a vaccine. Wong invented a process he calls programmable one-pot synthesis that allows him to quickly assemble many types of carbohydrate structures by placing a large number of chemical building blocks into a reaction vessel to make sequential chemical reactions.

So the Scripps Research team built a dendron structure that can bind to the DC-SIGN protein, preventing HIV from doing so, and which also mimics the sugar clusters that 2G12 binds to, prompting the immune system to produce destructive antibodies to the viral coat. \"The sugar structure is able to inhibit HIV from binding to DC-SIGN on dendritic cells in vitro,\" Wong said. \"But to become a vaccine, as tested in mice, the sugar structure has to be attached to a carrier as the sugar structure alone is too small and too weak to be used as a vaccine. The sugar-carrier conjugate will also inhibit HIV from binding to DC-SIGN.\"

The researchers say the next step in the research is to test if the dendron antibody can target the surface coating of different kinds of HIV strains in order to evaluate the potential of the vaccine strategy.

Other co-authors of the study are Pi-Hui Liang, Rena D. Astronomo, Tsui-Ling Hsu, and Shie-Liang Hsieh. The Skaggs Institute for Chemical Biology supported the work.
为了对抗HIV，Scripps的研究人员已经提出了一种新的策略，并且他们已经在实验室的成功的完成了验证。

研究者称，这项刚刚发表于国家科学院学报网络版的最新研究会再次鼓舞人们去开发对抗HIV的预防性或者治疗性的疫苗。至今为止，超过十几种试图提高对HIV病毒包膜上的蛋白免疫反应的候选疫苗在临床试验中均已宣告失败。

研究人员创造性地成功开发了一种被他们称为“glycodendrons”的方法，它会立刻产生两种效应：1、阻止HIV从常见的感染部位进入人体深部，那样会感染免疫细胞；2、刺激产生针对病毒表面糖类的特异性抗体。

这项研究的领导者，Scripps研究所化学教授Chi-Huey Wong说：“这项研究为HIV疫苗设计提供了一个新的方向，目前我们得到的结果令人充满希望。”

他还说，目前为止的结果显示，这种方法可以刺激小鼠的免疫系统，并诱导产生对抗HIV表面糖蛋白的抗体，从而阻止病毒感染免疫细胞。

HIV的一个多功能区作为靶目标

这种新方法利用了两项最近艾滋病毒研究领域的结果。一项是HIV通过木马程序来到达它要感染的人体细胞。科学家们描述道，当病毒通过性接触进入人体，它就粘附到免疫系统的树突状细胞上，这种细胞存在于组织粘膜内层起保护作用。

然而，病毒打败了这些细胞，并且阻断了树突状细胞表面的称为“DC-SIGN”的特异性受体蛋白。通过粘附到这些免疫细胞上，当树突状细胞转移到HIV的最终目标：T淋巴细胞时，病毒就成功的避免了免疫监视，这样病毒就侵入细胞，致命的感染就开始扩散。

该研究的第一作者，Wong 实验室的毕业学生Sheng-Kai Wang说：第二种发现是一种能够在病毒感染后预兆免疫系统遭到破坏的抗体。这种被称为2G12的抗体，能够阻止病毒感染进展，但是只有极少数的感染者会产生这种免疫反应。Scripps 研究所的科学家们已经发现的这种抗体产生的详情，还发现病毒表面敏感蛋白外壳上富含糖的区域明显与粘附树突状细胞上DC-SIGN 蛋白的区域是同样的区域。

早些时候，这项研究的合作者，Scripps研究所Dennis Burton教授和Wong教授设计并试验了人工合成了一个区域来模拟这个以2G12为标志的富糖类的区域，这可能会产生一种疫苗。Wong教授发明了一种被他称为“程序性一锅合成法”的方法，在反应器里通过大量的化学模块来产生连续的化学反应，这可以让他能够迅速的收集多种形式的糖结构。

因此，Scripps的研究小组建立了一个能够粘附DC-SIGN蛋白的树突状机构，来阻止HIV与DC-SIGN蛋白粘附，这样也模拟了富糖类区域2G12的粘附，从而促使免疫系统产生对病毒蛋白外壳有破坏作用的抗体。Wong 教授说：“在体外，这个含糖区域能够阻断HIV粘附到树突状细胞的DC-SIGN蛋白上。但是在小鼠身上试验时要成为疫苗，由于这个含糖区域太小以至于作为疫苗的作用过于弱，还需要连接到一个载体上。这个携带糖类的载体化合物也同样会阻止HIV粘附到DC-SIGN。”

研究者们说，研究的下一步是检测这个树突状抗体是否能够以不同种的HIV表面外壳为靶子，从而来评估它作为疫苗的潜力。

这项研究的其它合作者是Pi-Hui Liang, Rena D. Astronomo, Tsui-Ling Hsu, and Shie-Liang Hsieh。Skaggs研究所化学生物学组支持了此项研究。