图：巴基斯坦的HIV感染者无法得到有效治疗。

 

9月24日，美国和泰国研究人员宣布，双方合作开发试验的一种艾滋疫苗可以将人体感染艾滋病病毒的风险降低31.2%。这是人类首次获得具有免疫效果的艾滋病疫苗。

自从艾滋病毒（以下简称HIV）在1983年被法国巴斯德研究所的病毒学家、2008年诺贝尔生理学或医学奖得主吕克·蒙塔尼首次分离得到后，在对付这种疾病的征程中，人们始终在乐观和悲观的两极间徘徊。1984年，时任美国健康与人类服务部部长的玛格丽特·海格勒曾宣称，在两年内即可有疫苗上市，然而时至今日，在接二连三的失败打击下，美国国家过敏与传染病研究所所长安东尼·福奇悲观地表示，尽管尚未放弃，但我们可能永远也不会获得一种有效的HIV疫苗。

在时下疫苗的临床试验纷纷以失败告终的大背景下，美国军方和泰国公共卫生部联手进行的一项新型疫苗研究的进展似乎让我们看到了柳暗花明的一线曙光。

联合疫苗真的有效？

这项名为RV144的研究从2003年10月开始实施，是目前唯一参与人数逾万的HIV疫苗临床试验。科学家在泰国选取了1.6万余名年龄介于18~30岁间，HIV测试呈阴性且感染几率与普通人相似的志愿者参与研究，并将其分为疫苗组和安慰剂组。根据最新的研究结果，结果显示在8197名接受疫苗注射的志愿者中，有51人感染了HIV毒，而组成安慰剂组的8198人中，有74人感染，这意味着注射疫苗组感染风险降低了31.2%。并且科学家确信，这一差异具有统计学意义，并非是偶然因素引起的。

这种新型疫苗实际上应被归为联合疫苗的范畴，而其中组分恰恰是两种有过失败“前科”的旧疫苗——ALVAC和AIDSVAX。前者是一种重组的金丝雀痘病毒载体疫苗，包含有三个HIV基因，其设计初衷并不是为了避免感染，而是负责刺激免疫系统，通过细胞介导的免疫效应，使机体能够未雨绸缪，并在遇到HIV时能够发挥强力的抵抗作用，后者包含有一种重组的HIV表面蛋白gp120，它扮演的是助攻手的角色，起到增强免疫反应、加强攻击力度的作用。

2003年，这种疫苗开始在泰国进行I期和II期临床试验，实验结果表明，参与试验的健康受试者没有发生明显的不良反应，也没有人在实验过程中感染HIV。随后的评估认为，疫苗具备良好的药物耐受性并产生了免疫效果。

时至2006年，疫苗正式获批进入随机、双盲的III期临床试验阶段，接种时采取免疫-加强（prime-boost）的策略。即免疫组的健康志愿者在试验开始后的第0、1、3、6个月注射ALVAC疫苗，在3和6个月注射AIDSVAX。在随后的三年内每6个月进行一次HIV测试。

临床试验的结果甫一公布，顿时在业界掀起了轩然大波。就目前披露的信息来看，很多亟待回答的问题——针对不同的艾滋病病毒，针对不同人群，新型疫苗是否都有相同的免疫效果？新型疫苗的有效免疫期有多久？新型疫苗为何只表现出十分有限的免疫效果——依然没有明确的答案。此外对于已感染的人群，即便注射疫苗，免疫系统仍然面临被严重破坏的风险。WHO和UNAIDS在谨慎乐观之余也表示，仅凭现有的试验结果，尚不能批准疫苗付诸生产，也不能以此代替现有的HIV预防措施。以上种种未知因素和不足之处让人们在欣喜之余，不由得为攻克HIV的梦想打上了一个大大的问号。

徘徊了一亿年的幽灵

事实上，在这次临床试验结果公布之前，HIV疫苗研究正处于何去何从的十字路口。虽然历经数十年的研究，掩盖在HIV前的面纱被一层层地揭开，鸡尾酒疗法的横空出世似乎吹响了胜利的号角，仿佛最后的谜底就在眼前，但时不时就会“旧貌换新颜”的HIV却让不少科学家恍若自己就是滚石上山的西西弗斯。

迄今为止，有关HIV的传播，目前的看法是在二十世纪初非洲地区，病毒就由动物传播至人体内，传播的时间、地点及路径至今仍是未解之谜，但可以确定的是，HIV对哺乳动物的袭扰是一场横跨千万年的持久战。近日英国牛津大学的科学家在《科学》杂志上发表研究报告，他们声称，在霍氏树獭的基因组中发现了一种古老的HIV样病毒的序列，这意味着早在哺乳动物诞生伊始的一亿年前，HIV的祖先就已经开始发起攻击，这比人们以往的认识足足提前8500万年之久。

HIV的“老奸”还不是让人最为头疼之处，它的“巨猾”才是各种疫苗和治疗措施屡屡脱靶的症结所在。目前在人际间肆虐的主要是I型HIV，不过HIV-1就像一个大家族，其中还存在多种亚型。个中缘由盖因HIV拥有一个没有校正功能的逆转录酶。该酶是HIV复制所必须的关键酶，但与其他同类复制酶特点迥异的是，前者如同HIV生产流水线上的一台二手货一样，极易导致子代HIV发生突变，这使得HIV具有高度变异的特点。据估计，一位艾滋病患者体内荷载的病毒颗粒有1万~10万种之多。精确识别目标的中和抗体面对这种情况，仿佛陷入了人民战争的汪洋大海，由此HIV也获得了免疫逃逸的能力。

在与疫苗捉迷藏的过程中，狡猾的HIV其组成上保守位点往往隐藏在深处，包被在外部的序列却好似川剧中的变脸，一会儿一个模样，这让抗体即便与病毒相见，也未必能相识。HIV自身的结构也能赋予其种种优势。疫苗激发出的抗体在清除游离病毒时十分有效，但HIV的感染过程主要通过细胞融合——从一个细胞直接感染另一个细胞。这使得病毒与抗体根本打不上照面，有力使不出的抗体很难在其中发挥作用。此外组成HIV外膜蛋白gp120的一些氨基酸残基还能与一些糖类“狼狈为奸”，二者通过糖基化作用相结合后，就像为HIV蒙上一层厚厚盾牌一般，阻碍了抗体与病毒的中和。

非凡的变异能力赋予HIV逃脱抗体追捕的能力，在繁殖时，HIV似乎同样深谙一张一弛的文武之道。HIV感染的建立非常之快。有研究表明，通过性接触感染HIV-1数小时后，在阴道或直肠的粘膜下层就能检测到病毒，复制速度达到高峰时，每日体内能够产生出1011个新病毒颗粒。7天内全身淋巴组织的病毒载量就达到了慢性感染的水平。

为了能在人体内永续存在，HIV韬光养晦的本事也不小。在潜伏状态下，被感染细胞的膜上不会有病毒蛋白的表达，为期可达数十年之久，免疫系统很难识别这种“表面的平静”。本来免疫细胞是帮助人体对付外来异物的有力武器，但隐蔽本领了得的HIV偏偏以此为自己的藏身之所。对于抗体而言，这里无异于难以逾越的雷池。

在研究对付HIV的疫苗或药物时，困难不仅仅出自HIV自身的特殊性。缺少合适的动物模型同样是一个棘手的障碍。黑猩猩是除人类之外唯一能感染HIV的灵长类动物，但在人体内纵横捭阖的HIV到了黑猩猩体内却像被打蔫了一样，复制水平很低，不会引起任何艾滋病症状。另外作为濒临灭绝的珍稀动物以及人类的近亲，黑猩猩昂贵的价格以及伦理因素的存在对进一步研究起到了限制作用。

艾滋疫苗研究仍处于熊市

RV144研究结果面世之前的二十余年间，如同长江后浪推前浪一样，陆续共有四十多项HIV疫苗进入到了临床试验阶段，但毫无例外，被拍死在沙滩上是它们共同的命运。其中给世人打击最大的是美国默克公司的STEP新疫苗计划。这种被誉为HIV疫苗研究史上最先进也最有前途的疫苗在2007年止步于II期临床试验。当年9月，《科学》杂志遗憾地宣布疫苗研究折戟沉沙的坏消息后，全世界HIV疫苗的研究如同彼时的股市一般，开始步入绵绵阴跌的熊市阶段。

如何摆脱施加于西西弗斯身上的恶咒，不久前，《自然·医学》杂志的资深编辑克莱尔·托马斯采访了25位艾滋病研究领域的权威研究者，希望从他们头脑风暴中提炼出答案。不过熊市不言底的铁律依然生效—他们的共同结论是“有效的HIV疫苗似乎在未来10至15年内不会被发现。”

然而与此同时，他们也表示，虽然艾滋病的研究已经跨越了艰难坎坷的雄关与漫道，但鉴于对艾滋病发病机理的基础机制仍旧理解不足，揭开终极答案的必由之路似乎是自基础研究开始重头翻越。正如托马斯在《艾滋病研究的拦路虎》一文中提到的那样，美国宾夕法尼亚大学医学院的Michael Betts用俗谚“旁观者清”来建议大家跳出当前的窠臼，重新审视HIV疫苗的研究。

本文作者风之桦 系四川大学生物治疗国家重点实验室博士，科学松鼠会成员。 (本文来源：南都周刊 作者：风之桦)

The authority of 25 AIDS researchers: 15 years, were unable to find an effective vaccine
2009-10-17 10:18:05 Source: Nanfang Wang
Not long ago, "Nature Medicine" magazine's senior editor Claire Thomas interviewed 25 researchers the authority of the field of AIDS research, hoping to storm their minds to extract the answer. But the bear market is not made at the end of the iron law remained in force - their common conclusion that "an effective HIV vaccine appears in the next 10 to 15 years will not be found."




Figure: Pakistan HIV-infected people can not get effective treatment.



September 24, the U.S. and Thai researchers announced that they develop an HIV vaccine trial could be the body reduce the risk of HIV infection 31.2%. This is the first time with the immune effect of the human AIDS vaccine.

Since the HIV virus (hereinafter referred to as HIV) in 1983 by the French Pasteur Institute virologist, 2008 Nobel Prize in Physiology or Medicine Prize winner Luc Montagnier isolated the first time, after the journey in dealing with this disease , people are always optimistic and pessimistic wandering between two poles. In 1984, the then U.S. Department of Health and Human Services Minister Margaret Haegele has claimed that in two years can have a vaccine available, but today, in the failure of successive blow, the United States National Institute of Allergy and infectious Disease Research Institute, said Anthony Fauci, pessimistically, although not abandoned, but we may never have access to an effective HIV vaccine.

In today's clinical trials of vaccines have failed the backdrop, the U.S. military and the Thai Ministry of Public Health conducted a joint study of the progress of new vaccines seemed to us a ray of hope to see a way out.

Combined vaccine is really effective?

The study, called RV144 from the start in October 2003, is the only number of participants in HIV vaccine clinical trials, Yu Wan. Scientists in Thailand have selected 1.6 thousand women aged between 18 and 30 between the ages of, HIV infection tested negative and the probability of ordinary people like the volunteers participated in the study and divided into the vaccine group and the placebo group. According to the latest results of the study results showed that in the 8197 vaccinated volunteers, 51 people were infected with HIV drugs, which consists of the placebo group of 8198 people, 74 people are infected, which means that infection in vaccinated group risk reduction of 31.2%. And scientists are confident that this difference was statistically significant, is not accidental factors.

This new vaccine should actually be classified as a combined vaccine category, of which there have been two kinds of components is precisely the failure of "criminal record" of the old vaccine - ALVAC and AIDSVAX. The former is a recombinant canary pox virus vector vaccine contains three HIV genes, which was originally designed not to prevent infection, but are responsible for stimulating the immune system through cell-mediated immune response, so that the body be able to plan ahead, and HIV in the face of strong resistance when you can play the role, which includes a reorganization of the HIV surface protein gp120, which is playing the role assists hand, would serve to strengthen the immune response, efforts to strengthen the role of attack.

In 2003, this vaccine began in Thailand I phase and II clinical trials, experimental results show that healthy subjects participated in the experiment no significant adverse reactions, and no one in the experiment during the infection of HIV. The subsequent assessment that the vaccine has a good drug tolerance and produce an immune effect.

Time to 2006, formally approved the vaccine into the randomized, double-blind Phase III clinical trials, the vaccination to take immune - to strengthen the (prime-boost) strategy. Immuno-group trial in healthy volunteers after the start of the first 0,1,3,6-month injection of ALVAC vaccine, at 3 and 6 months, injected AIDSVAX. In the ensuing three years, once every 6 months, HIV testing.

As soon as he announced the results of clinical trials, immediately set off a firestorm in the industry. The disclosure of information on the current terms, many urgent questions to answer - for different AIDS virus, for different groups of people, the new vaccine have the same immune effect? New vaccines and effective immune period is how long? Why the new vaccine has shown only very limited immune effect - is still no clear answer. In addition, populations that had been infected, even if vaccinated, the immune system is still faced the risk of being severely damaged. WHO and UNAIDS are cautiously optimistic I also said that the existing test results alone, not yet approved the vaccine put into production, it can not be used to replace the existing HIV preventive measures. All these unknown factors and shortcomings so that people excitedly could not help but dream of for the capture of HIV branded a big question mark.

Wandering ghost of the Yi Yinian

In fact, before the publication of the results of clinical trials, HIV vaccine research is at a crossroads. Despite decades of research, to cover up in front of the veil has been a HIV layers to be opened, turned out to cocktail therapy appears to have blown the horn of victory, as if the last mystery at hand, but from time to time will be the "old appearance Huanxin Yan, "HIV-Querang Many scientists reminding us of scenes that he is the Rolling Stone of Sisyphus uphill.

So far, the spread of HIV, the current view is that in the early twentieth century Africa, the virus spread from animals condemns individuals to the body, the spread of time, place and the path is still an unsolved mystery, but one thing is HIV is a harassment of the mammals across millions of years, a protracted war. Recently, scientists at the University of Oxford in the "Science" magazine published research reports, they claim, in the Khodorkovsky sloth found in the genome of an ancient HIV-like virus sequences, which means that as early as the beginning of the birth of a mammal million years ago, HIV's ancestors had begun to attack, more than a full understanding of the people in the past 8500 million years ahead of schedule.

HIV "old rape" is not the headache of at most people, it's "Giant Kid" is a variety of vaccines and therapeutic measures often the crux of off-target. At present interpersonal raging mainly I-type HIV, but HIV-1 is like a big family, of which there are a variety of subtypes. Secondary reason Gein HIV do not have a correction function of reverse transcriptase. The enzyme is necessary for HIV replication key enzyme, but other similar replicase characterized by very different is that the former as the HIV on the production line, like a second-hand goods, easily lead to a mutation in HIV progeny, which makes HIV has a high level of mutated characteristics. It is estimated that an AIDS virus-like particles in vivo load of 1 million to as many as 100,000 kinds. Precisely identify the target of neutralizing antibodies to face such a situation, as if caught in the vast ocean of people's war, thus also received HIV immune escape capabilities.

Hide and seek with the vaccination process, the composition of HIV-cunning conservative sites are often hidden in the depths of the package was in the external sequence in the Face of Sichuan Opera is as if, while an appearance, which make antibodies, even with the virus each other, may not be met. The structure of HIV itself can give it many advantages. Vaccines stimulate antibodies in the clearance of free virus is very effective, but the process of HIV infection primarily through cell fusion - from one cell to another cell directly infected. This makes the virus and antibodies to fight simply is not on the face to face, strong so that no antibody is difficult to play a role. In addition, the composition of some of the HIV membrane protein gp120 amino acid residues also with some sugar, "working hand in glove", both through the combination of glycation, after casting a thick layer as a shield for HIV in general, prevented antibody and virus neutralization.

The extraordinary variability of HIV to escape antibody gives the ability to hunt during the breeding time, HIV appear to be equally well versed in a way a relaxation of the civil and military. The establishment of HIV infection is very fast. Studies have shown that infection through sexual contact with HIV-1 a few hours later, in the vagina or rectum can be detected in the submucosa of the virus replication rate reached a peak day when the body can produce 1011 new virus particles. Within 7 days of systemic lymphoid tissue viral load reached the level of chronic infection.

To be able to continue uninterrupted in the human body, HIV status-quo of no small ability. In the latent state, the membrane of infected cells no viral protein expression, for a period of up to several decades, the immune system difficult to identify such a "surface calm." Originally immune cells help the body to deal with external foreign body in a powerful weapon, but the hidden ability of HIV terrible happens this as their hideouts. For the antibody is concerned, here is tantamount to insurmountable perimeter.

In the study of vaccines or drugs against HIV, the difficulties were not from the special nature of HIV itself. Lack of appropriate animal models is also a difficult obstacle. In addition to humans than chimpanzees are the only primates infected with HIV, but HIV-maneuvers in the human body to body like a chimpanzee was Danian of the same low level of replication does not cause any symptoms of HIV. In addition, as endangered rare animals and close relatives of humans, chimpanzees, high prices and the existence of ethical factors played a limited role in further study.

HIV vaccine research is still in a bear market

RV144 research results available before the 20-plus years since, as the waves pushed forward, like waves, one after another a total of 40 number of HIV vaccine has entered clinical trials, but without exception, was shot dead on the beach is their common destiny. One to the world hardest hit is the U.S. Merck's STEP program for new vaccines. This known as the HIV vaccine research in the history of the most advanced and most promising vaccine in 2007, stop at the Phase II clinical trials. Year in September, "Science" magazine regret to announce the bad news sink like a stone for Vaccine Research, the world's HIV vaccine research in general, as the stock market wound up and entered into the rain, Yindie bear market phase.

How to get rid of the evil imposed on the Curse of Sisyphus who, not long ago, "Nature Medicine" magazine's senior editor Claire Thomas interviewed 25 researchers the authority of the field of AIDS research, hoping to storm their minds to extract the answer. But the bear market is not made at the end of the iron law remained in force - their common conclusion that "an effective HIV vaccine appears in the next 10 to 15 years will not be found."

But at the same time, they also said that while AIDS research has spanned a difficult rocky with big and diffuse Road, but in view of the basic mechanism of AIDS pathogenesis is still lack of understanding, the only way to reveal the ultimate answer seems to be the first since the basic research are beginning to climb over . As Thomas in "The stumbling block AIDS research," as mentioned in a paper, University of Pennsylvania School of Medicine Michael Betts with the Chinese saying, "spectators" to suggest that you jump out of the current cocoon, and to re-examine HIV vaccine research.

The author of the Wind Cheng University, Sichuan University, State Key Laboratory of Biotherapy, Dr., Scientific squirrel members. (This article Source: South Du Weekly Author: Wind Hua)