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Combing Through HIV's Family Tree for Ways to Block
"Immune Escape"
Bruce D.
Walker
In the battles that rage between the human
immunodeficiency virus (HIV) and an infected patient's T cells, the
rules of engagement are always changing. The T cells adapt
continuously to recognize HIV proteins and alert the immune system
to launch an attack. But the virus perseveres because it has an
exceptional capacity to mutate - to take on mutant forms that can
escape immune surveillance.
Immune escape renders HIV more dangerous because
the virus cannot be reigned in by the immune system. As researchers
work toward developing a vaccine that will assist the immune system
in its battle against HIV, they want to know exactly which
mutations enable the virus to evade detection.
Researchers had initially believed that by
cross-sectionally analyzing mutations in HIV one could define those
that had arisen as a result of immune escape, and pinpoint regions
of the viral genome that are important for recognition by T
cells.
New research by a team of scientists that includes
Howard Hughes Medical Institute investigator Bruce Walker has now
established that the accuracy of this type of analysis can falter
due to the many subtypes of HIV that circulate globally. This is
because some of the mutations represent historical subtype or
lineage differences rather than mutations that have arisen as a
result of immune selection pressure.
Walker and his colleagues have found that
identifying the presence of these multiple lineages of HIV can
greatly improve the accuracy of the genetic analyses. Furthermore,
statistical methods for elucidating such phylogenetic relationships
among viral genome sequences will give virologists new insights
into the evolution of viruses and how viruses alter themselves as
they adapt to the immune system.
The researchers published their new approach in the
March 16, 2007, issue of the journal Science. Bette Korber
of Los Alamos National Laboratory and the Santa Fe Institute was
the senior author of the article. Walker is at the Partners AIDS
Research Center of Massachusetts General Hospital, Harvard Medical
School. Other co-authors were from Microsoft Research, the
University of Washington and Royal Perth Hospital in Australia.
In a previous study, co-author Simon Mallal and
colleagues at Royal Perth Hospital revealed that viral genetic
sequences isolated from a group of patients in Perth showed clear
evidence for host-driven immune selection during infection.
“That was a seminal study,
because it showed that the biology of the human immune system was
impacting how HIV was evolving because of these immune genes,”
said Korber. “But the methods used didn't take into account the
possibility that different lineages of virus might be present, and
might affect the analysis,” she said.
“The challenge for HIV vaccine
design is to determine the precise mutational pathways the virus
uses to escape detection,” Walker said. “Existing methods did not
differentiate between actual immune escape and historical
differences in the HIV subtypes.”
In the new study, Korber, Walker and their
colleagues reanalyzed the Perth data using a new statistical
technique that could trace how multiple genetic subtypes of the
virus had evolved in individual patients. Taking these lineage
effects into account, said Korber, led to “a very different
portrait of the specific nature of the immune selection than they
had reported in the original paper.”
The researchers focused on the viral genes for two
HIV proteins. The genetic portrait that emerged from those
experiments revealed that the sample — formerly believed to be
homogenous — actually contained more than one genetic subtype of
the virus. The presence of multiple subtypes would compromise the
accuracy of the genetic analysis, said Korber and Walker. Even
within these subtypes, the researchers found genetically distinct
“subclusters” that would further compromise the accuracy of
genetic analyses of immune escape. The new methodology should
improve the accuracy of future analyses by taking into account
phylogenetic relationships among viral genetic sequences, they
said.
“These new bioinformatics
techniques, together with functional immunology data being
generated in real time as the epidemic expands, will be critical
for HIV vaccine design to deal with the tremendous variability of
the virus,” said Walker.
“This methodology is generally
applicable to other viruses and to other HIV studies,” said
Korber. “For example, my colleagues and I are now using it to ask
whether at the moment of transmission, there are genetic
differences in the transmitted virus, compared to the virus that
exists in a chronic infection. All of this kind of information can
help vaccine developers make informed decisions about what
components need to be included in a vaccine to give maximum
population coverage.”
Korber said the new analysis also indicated that
the same genetic characteristics of HIV that may enable the virus
to escape immune detection in one person may make the virus
susceptible to detection in another person. Such insights will also
be important in formulating vaccines with sufficient variation to
be maximally effective in many people, she said. “If you have
those variants in a vaccine, you might not only be able to get
better population coverage in the first place but you might be able
to block common immune escape routes,” she said.
“This project is a great example
of people from multiple disciplines working together to gain new
insight into a disease that is devastating large areas of the
globe,” said Walker.
Korber and her colleagues are now applying their
method to analyze the genes for all of the proteins produced by the
HIV genome, besides the two reported in the Science study,
to gain further insights into the machinery of immune escape.
通过结合HIV族谱寻找阻断“免疫逃避”的途径
Bruce D.
Walker
布鲁斯-沃克
在每一位其感染患者的T细胞和人类免疫缺陷病毒间的艰难博弈中，互相间的规则总是变幻无常。T细胞采用持续识别HIV蛋白的策略使免疫系统处于警觉状态对HIV发动攻击。但是病毒却是“野火烧不尽，春风吹又生”，因为其进行突变的特殊能力－HIV的突变体能逃脱（人体）免疫监视
因为人体免疫系统不能对付HIV，免疫逃避致使该病毒具有更大的危险性。当研究人员致力于发展一种协助免疫系统对付HIV的疫苗时，他们希望准确知道是哪种突变使
HIV逃避清除的。
研究人员最初相信，通过对HIV突变横断面分析，他们能限定这些最终导致免疫逃避的突变，而且能精确找到病毒基因组中对于T细胞识别重要的序列。
霍华德-休斯医学研究所研究员布鲁斯-沃克参与的一个科学家团队进行的研究确认，由于在整个循环中HIV亚型众多，因此该分析的准确性受到影响。这是因为其中一些突变代表了以往发展而来的亚型或家族血缘差异，而不是作为免疫选择压力结果而产生的突变。
沃克和同事们发现对这些HIV多家族性（突变）存在的鉴别可非常大提高（对HIV突变）遗传分析的准确性。进而，在病毒基因组序列间阐明这种多种系发生关系的统计学方法将给病毒学家对病毒进化提供新的视角，以及病毒如何通过改变自身（突变）适应人体免疫系统。
研究人员在2007年3月16日《科学》杂志上发表了他们新方法。洛斯阿拉莫斯实验室和圣菲研究所的贝特·科伯是这篇文章的资深作者。沃克是哈佛医学院马萨诸塞州总医院配偶艾滋病研究中心的负责人。其他的合作者来自微软研究公司，华盛顿大学以及澳大利亚皇家珀斯医院。
在前期的研究中，皇家珀斯医院的合著者Simon
Mallal和同事发现，在珀斯一组患者上分离的病毒遗传序列显示明确的证据，即在HIV感染中存在宿主驱动的免疫选择（压力）。
科伯说：“这是一个开创性研究，因为该研究显示在人类免疫系统生物学影响下因为这些免疫基因HIV是如何进化的。但是使用的该方法没有考虑不同病毒品系共存的可能性，而这或可对分析有影响。”
沃克称，HIV疫苗设计的挑战在于确定病毒逃避清除的准确突变方式，但是现有的方法不能区分来自实际免疫逃避和由历史发展分化而来的HIV亚型。
在本新研究中，科伯、沃克和他们的同事使用新的统计手段对来自珀斯的资料重新分析，可以追踪个体患者体内有多少多病毒遗传亚型。科伯称，将这些族谱效应考虑进去，导致“与最初文献报告相比，免疫选择的特殊本质特征有非常大的差异。”
研究人员着重研究了两种HIV蛋白的病毒基因。这些实验出现的遗传特征显示，HIV样本－先前认为是来自同族的－实际上包含一个HIV遗传亚型以上。沃克和科伯称，多HIV亚型的存在削弱遗传分析的准确性。甚至在这些亚型中，研究人员发现遗传学上不同的“亚系”将导致免疫逃避遗传学分析的准确性进一步降低。他们说，这种新的方法考虑到多种系发生的关系将提高未来分析的准确性
沃克说：“这些新生物信息学技术，结合流行病扩充实时产生的功能免疫资料，对具有非常大变异性能力的HIV疫苗设计至关重要。”
“该方法普遍适用其他病毒和其他HIV研究，”科伯说：“例如，同事和我正使用这种方法探询在传染时，与慢性感染中存在的病毒相比，传染的HIV是否有遗传差异。所有这类信息将帮助疫苗设计者作出合理决策，一种可产生最大人口覆盖的疫苗应该包括那些（遗传）成分。
科伯说，该新分析法还指出相同的HIV遗传特性或能使病毒在一位患者身上逃避免疫清除，而在另一位患者上则是易被清除。她说，这样的观点对疫苗形成非常重要，这种疫苗具有充分变异，能在大多数人上起最大效应。
沃克说：“该项目是来自多领域科学家共同努力的绝佳例证，为正泛滥全球的AIDS提供了全新认识。”
科伯和她的同事正运用他们的方法分析HIV基因组中所有产生的蛋白的基因，包括在《科学》杂志发表的两个报道外，进一步获得对免疫逃避机制的认识。
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