30年艾滋病研究的成功和失败

自从第一例艾滋病报告以来，整整三十年过去了，在艾滋病疫苗、药物和治疗方面科学界有了很大的突破。这不仅仅是因为像比尔和梅琳达盖兹基金会这样的资金大腕投入了数以百万计的资金，更重要的是30年来的科学研究使人类对艾滋病病毒有了深入的认识。

在遗传学、药物载体、疫苗、计算机模型和其他不同学科上的突破都使人类更深入的认识这种疾病，甚至最近的疫苗失败也为研究打开了新路径。

Global HIV Vaccine Enterprise的执行董事Alan Bernstein最近对路透社记者说，“现在是艾滋病毒疫苗研究的关键时刻，过去五年是疫苗研究最多的时期。现在的问题是。。。我们在这些科学进步的基础上该做些什么？”他补充说，科学家们跨国界和跨学科的合作是至关重要的。

要彻底战胜这一疾病，我们仍旧有很多工作要做，但是重点已经改变，研究正在向前推进。随着抗逆转录病毒药物组合的治疗、可能的预防措施以及重新兴起的疫苗寻找工作，艾滋病最终将会同天花一样走进历史的垃圾堆。

疫苗

镶嵌疫苗（Mosaic vaccine，也叫马赛克疫苗）

艾滋病毒进化能力超强。所有那些科幻片里描述的那些失控的机器智能似乎在刚开始时能被打败，但是接下来他们能够适应那些用来对付他们的武器而变得更加强大。这就是艾滋病毒的作用原理，它就是这样挫败和阻挠那些人类已经找到的对付它的武器。

答案是世上没有一个单独的终极武器可以被用来对抗艾滋病毒。当前的疫苗研究告诉了我们这一点。下一代的艾滋病疫苗称作为“镶嵌疫苗”。它们是由很多人工合成、计算机生成的蛋白序列组成，可以促使免疫系统对不同的病毒菌株作出反应。这种疫苗已经在动物研究中成功，新的实验将测试镶嵌疫苗的概念以及是否可能产生下一代的艾滋病毒候选疫苗。

一个新的，部分由比尔和梅琳达盖茨基金会资助的财团正在试图在2012年底推出一个镶嵌疫苗的实验。

泰国实验（Thai trial）

一个几乎每个在艾滋病发展中都引用的成功的疫苗试验，通常被称为“泰国实验”。这个在泰国进行的RV 144疫苗试验始于2003年，于2006年结束，2009年发布研究结果。接受疫苗的人群相对于接受安慰剂的，艾滋病毒感染率下降了31％，这一结果使得许多人宣称RV 144是第一个有证据表明可以降低感染艾滋病风险的疫苗。

试验中首先接种的疫苗是ALVAC-HIV,它由一个包含有3个艾滋病毒基因（env、gag和pro）的基因工程载体组成，由赛诺菲巴斯德公司生产。增强疫苗是由Genentech根据与VaxGen的许可和供货协议生产的。

这种方法被称为“初始/加强(prime boost)”,它要求先注射一种类型的疫苗，然后紧接着再注射第二中疫苗。这样做是为了增强机体对病毒的免疫反应。

泰国试验目前正作为一种模式被仔细研究，用于未来开发疫苗。

Crucell

由于受到泰国试验结果的鼓舞，荷兰生物技术公司Crucell正与合作者联合开发一个prime-boost疫苗。与哈佛大学Beth Israel Deaconess医学院和Ragon研究所的科学家们合作，Crucell计划将它的疫苗以prime-boost的方法用于一名国际艾滋病疫苗行动组织(IAVI)推荐的候选人。研究人员将跟踪该组合疫苗的安全性，以及它是否能够在健康志愿者身上激发免疫反应。

如果I期试验获得成功，Crucell称他们将继续开展临床IIb期研究。这项研究得到了美国国家过敏与传染病研究所(NIAID)的支持。强生公司希望能收购Crucell，以推动其自己的疫苗项目。

失败和新的机会

当涉及科学时，虽然我们知道一个新兴的科学不一定适用于绝对的方式，然而主流媒体往往趋向与用绝对的方式来处理。一项研究建立在另一项研究的基础上，而另一项研究又建立在另外的一项研究上（有时甚至跨越几十年），直至一个清晰的画面出现。当科学发展到达了一个阶段，有实质性的潜在重磅产品，如艾滋病疫苗，被测试，“通过/失败”评价体系宽恕了媒体。产品或者通过，或者失败，在这里不会存在细微的差别。公司试图公开上市疫苗，药品试验就像赛马比赛，或者胜利或者失败，同时伴随着股票价格的上涨与下跌。

2007年，美国默克公司的STEP艾滋病疫苗在临床IIb期失败，迫使这家制药巨头放弃艾滋病疫苗项目。该临床试验测试了HIV-1 B亚型疫苗MRKAd5，由来自于多个国家的3000名患者参与。疫苗的本来设想是通过激发机体产生白细胞来识别和定位HIV-1的特异基因Gag、Pol和Nef。最初的试验表明该疫苗能够触发所期望的病毒攻击细胞的形态。然而，第一个中期分析显示，这个疫苗及不能阻止HIV-1的传染，也不能减少体内的病毒载量，因而停止了接种。

故事结束了吗？并不是。

现在，华盛顿大学（University of Washington）微生物学教授James Mullins和他的团队分析了68名参加STEP疫苗接种后新感染艾滋病的志愿者的HIV-1的基因序列。该研究小组测试了“筛子效应”，Mullins解释说，这种情况就是一个疫苗成功地阻断了一些病毒株，却不能阻断其他病毒株。

这是首次证明疫苗诱导的细胞免疫反应在对抗HIV-1感染时对病毒具有选择性压力。选择性压力是指环境需求对于某些特定的遗传性状相对于其他性状更为有利。研究人员补充说，他们的研究结果表明，新疫苗必须将其在病毒上的选择性压力置于可控制的范围内。

这就是科学的真正道路。以前的失败指引了新的探寻途径。

抗逆转录病毒药物组合

值得庆幸的是，在过去30年与艾滋病毒的斗争中，有一件事发生的改变，那就是，确诊艾滋病不再意味着立即宣判死刑。如果，你还能负担得起治疗费用的话。就如同寻找疫苗一样，治疗艾滋病毒感染的药物也需要比病毒快速适应和进化的能力更快一步。

有一段时间，出现了一系列很难发音的药物组成了鸡尾酒治疗，这些药物包括齐多夫定、拉米夫定、阿巴卡韦和恩曲他滨等。最近，制药公司已经将这些复杂的鸡尾酒药物组合联合成简单的、固定剂量的复方抗逆转录病毒药物。

最畅销的艾滋病抗逆转录病毒复方药物是Gilead的Truvada。其他销量较好的此类药物有Gilead和BMS的Atripla，GSK的Combivir以及雅培的Kaletra。

虽然抗逆转录病毒复方药物对艾滋病毒阳性患者来说是革命性的，但是它们还是有很多缺点。这些药物有严重的副作用，如果患者忘记服用，病毒就会产生耐药性，而且这些药物非常昂贵以至于世界上大多数的艾滋病感染者无法负担治疗费用。

使用抗逆转录病毒药物来预防艾滋病

几十年过去了，已知的的预防方法已经不仅仅局限于禁欲或者使用避孕套。现在，抗逆转录病毒复方药物正在被测试是否具有预防的功能。事实上，尽管很多医生不大愿意，仍有有许多此类药物，比如Truvada，已经被医生在批准适应症外应用于预防艾滋病。

最近的一项研究表明，Truvada能够在接触病毒后有44％的可能性保护高危患者，虽然随后的研究发现这个药物在妇女身上未能产生同样的作用。

尽管如此，世界卫生组织对此事持鼓励态度，而且艾滋病活动家也对此很积极。有更多的研究正在进行中。

[原文]FierceBiotech

Successes, failures mark 30 years of HIV/AIDS research

May 24, 2011 — 7:29am ET ｜ By Howard Lovy

It is difficult to put your finger on why, almost exactly three decades after the first case of AIDS was reported, there is now a general feeling in the scientific community that big breakthroughs are coming soon in AIDS vaccines, treatments prevention. It is not only that big financiers like the Bill & Melinda Gates Foundation are contributing millions to the eradication of HIV (although that certainly helps). It‘s that the 30 years spent on understing the virus that causes AIDS is at last making sense in a coherent way.

Breakthroughs in genetics, drug delivery, vaccines, computer modeling other disparate disciplines are all converging onto their target. Even recent vaccine failures have opened up new avenues of inquiry.

"This is a pivotal moment in HIV vaccine research," Alan Bernstein, utive director of the Global HIV Vaccine Enterprise, recently told Reuters. "The last five years have been the richest period in HIV vaccine research since the epidemic began. The question...now is how do we build on these scientific advances?" He added that cross-border cross-discipline collaboration among scientists was crucial.

Much work still needs to be done to rid the world of this modern-day plague that has cost so many lives, but it seems to be with renewed focus, AIDS research is moving forward. With antiretroviral combination drugs as treatment possibly prevention, a reinvigorated vaccine search, it is possible that HIV/AIDS could eventually go the way of smallpox into the dustbin of history.

Vaccines

‘Mosaic‘

HIV, the virus that causes AIDS, has a frustrating ability to evolve rapidly. Think of all those science-fiction movies where some sort of out-of-control machine intelligence seems to be defeated at first, then comes back stronger as it adapts to the weapons used against it. That is what HIV does, how it frustrates foils those who think they have found a single weapon to use against it.

The answer, then, is that there is no single ultimate weapon that can be used against HIV. And that is where current vaccine research is taking us. The next generation of HIV vaccines are known as "mosaics." They are composed of many sets of synthetic, computer-generated sequences of proteins that can prompt the immune system to respond to a variety of strains. Such vaccines have shown success in animal studies, new trials will test the mosaic concept could possibly lead to the next generation of HIV vaccine cidates.

A new consortium, funded in part by the Bill & Melinda Gates Foundation, is trying for a Mosaic vaccine, hoping to launch trials by late 2012.

Thai trial

The one vaccine trial that just about everybody who follows HIV developments references as a success is commonly known as the "Thai Trial." It was a vaccine trial in Thail known as RV 144 that began in 2003 ended in 2006, with results released in 2009. Those who received the vaccine saw a 31 percent drop in HIV infection compared to those who received placebo, prompting many to RV 144 the first vaccine to give any supporting evidence of having lowered the risk of contracting HIV.

The prime vaccine was ALVAC‐HIV, which consisted of a viral vector of genetically engineered versions of three HIV genes (env, gag pro). It is manufactured by Sanofi Pasteur. The booster vaccine was manufactured by Genentech under a license supply agreement with VaxGen.

The approach the trial took is known as "prime boost," which is essentially administration of one type of vaccine followed by a second type. The idea is to enhance the body‘s immune responses to the virus.

The Thai trial is being studied closely as the model for future development of a final vaccine.

Crucell

Building on the encouraging results of the Thai trial, Crucell is joining with a host of collaborators to develop a prime-boost combination vaccine. Working with researchers from Harvard University‘s Beth Israel Deaconess Medical School the Ragon Institute, the Dutch biotech plans to mix its vaccine with a cidate from the International AIDS Vaccine Initiative in the prime-boost approach. The investigators will track the combination vaccine‘s safety as well as its ability to provoke an immune response among healthy volunteers.

If the Phase I trial is successful Crucell says they can pursue plans to mount a proof-of-concept Phase IIb study. The research work is supported by the National Institute of Allergy Infectious Diseases. It might have been Crucell‘s work on the AIDS vaccine that convinced Johnson & Johnson that it wanted to buy Crucell, in part to boost its own vaccine program.

Failures new opportunities

Even when covering science, the mainstream media tend to deal in absolutes--even though we know that an emerging science does not necessarily work in absolutes. One study builds on another, which builds on another until--sometimes over a period of decades--a clear picture emerges. But the media can be forgiven a "pass/fail" rating system when science reaches the point where actual potential blockbuster products, like AIDS vaccines, are tested. It either passes or it fails, there does not appear to be much nuance there. And add to the fact that the company trying out its vaccine is publicly traded, the financial press steps in to frame a drug trial as a horse race, either a victory or defeat for the company, with accompanying ups downs in stock prices.

This is what happened to Merck back in 2007, when failure of its STEP HIV vaccine in Phase IIb trials forced the drug giant to scrap the vaccine program altogether. The multinational, 3,000-patient Phase trial tested a Merck HIV-1 subtype B vaccine known as MRKAd5. It was designed to make the body produce white blood cells that could recognize target specific parts of HIV-1 known as Gag, Pol Nef. Preliminary tests indicated the vaccine was encouraging the appearance of the desired virus-attacking cells. However, immunizations were halted after the first interim analysis indicated that the vaccine neither prevented HIV-1 infection nor reduced the load of virus in the body.

End of story, right? Not quite.

Now, James Mullins, University of Washington professor of microbiology, his a team have analyzed the genome sequences in HIV-1 isolated from 68 newly infected volunteers in the STEP trial. The research team tested for a "sieve effect," which, Mullins explains, occurs when a vaccine successfully blocks some strains of virus not others.

This is the first evidence that vaccine-induced cellular immune responses against HIV-1 infection exert ive pressure on the virus. "Selective pressure" refers to environmental dems that favor certain genetic traits over others. The researchers added that their findings suggest that new vaccines should be designed to put ive pressure on the virus in a controlled manner.

This is the way science really works. Old failures lead to new avenues of inquiry.

Combination Antiretrovirals

Thankfully, one thing that has changed in 30 years of dealing with the AIDS virus is that a diagnosis is no longer an immediate death sentence. Well, that is, for those who can afford the treatment. As with the search for a vaccine, medication to treat HIV infection needs to stay one step ahead of the virus‘s ability to quickly adapt evolve.

For a while, these came in the form of cocktails of hard-to-pronounce names like zidovudine, lamivudine, abacavir, emtricitabine others. More recently, drug companies have combined these complex cocktails into simpler, fixed-dose combination antiretroviral drugs.

The biggest selling of all the combination HIV retrovirals is Truvada, by Gilead. Others are Atripla, produced by Gilead Bristol-Myers Squibb, Combivir by GlaxoSmithKline Kaletra by Abbott Laboratories.

While antiretroviral combination meds have revolutionized care of HIV-positive patients, they do come with many drawbacks. The drugs can have serious side effects, the virus can build resistance to them if the patient misses doses, they are so expensive that the majority of the world‘s infected population can‘t afford treatment.

Antiretroviral drugs as prevention

For decades, the only known preventative has been either abstinence or use of condoms. Now, that may be changing as antiretroviral combination drugs are being tested for their preventative power. Indeed, many--like Truvada--are already being prescribed off-label for prevention, despite reluctance of many doctors to prescribe such an expensive drug.

A recent study showed that Truvada prevented high-risk patients from contracting the virus 44 percent of the time, although a subsequent study showed that the drug failed to produce the same kinds of results for women.

Still, the World Health Organization is encouraging on this issue, AIDS activists appear to be excited about it. More studies are underway.

来源：新浪博客（http://blog.sina.com.cn/s/blog_4468f9470100s27l.html）