在每一位感染患者的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HIV的突变体能逃脱免疫监视。
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以在很大程度上提高遗传分析的准确性。进而，在病毒基因组序列间阐明多种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》杂志上发表了他们的新方法。
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的生物学影响下这些免疫基因HIV是如何进化的。但是使用该方法没有考虑不同病毒品系共存的可能性，而这可能对分析有影响。”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，先前认为是来自同族的HIV样本实际上包含一个以上HIV遗传亚型。沃克和科伯称，多HIV亚型的存在削弱了遗传分析的准确性。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，产生最大人口覆盖的疫苗应该包括哪些遗传成分。”
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，而在另一位患者身上则易被清除。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，能在大多数身上起最大效应。沃克说：“该项目是来自多领域科学家共同努力的绝佳例证，为正在全球泛滥的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基因组中所有产生蛋白的基因，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。
部分英文原文：
原文一：
Science 16 March 2007:
Vol. 315. no. 5818, pp. 1583 - 1586
DOI: 10.1126/science.1131528
Founder Effects in the Assessment of HIV Polymorphisms and HLA Allele Associations
Tanmoy Bhattacharya,1,2 Marcus Daniels,1 David Heckerman,3 Brian Foley,1 Nicole Frahm,4 Carl Kadie,3 Jonathan Carlson,3,5 Karina Yusim,1 Ben McMahon,1 Brian Gaschen,1 Simon Mallal,6 James I. Mullins,7 David C. Nickle,7 Joshua Herbeck,7 Christine Rousseau,7 Gerald H. Learn,7 Toshiyuki Miura,4 Christian Brander,4 Bruce Walker,4,8 Bette Korber1,2*
Escape from T cell–mediated immune responses affects the ongoing evolution of rapidly evolving viruses such as HIV. By applying statistical approaches that account for phylogenetic relationships among viral sequences, we show that viral lineage effects rather than immune escape often explain apparent human leukocyte antigen (HLA)–mediated immune-escape mutations defined by older analysis methods. Phylogenetically informed methods identified immune-susceptible locations with greatly improved accuracy, and the associations we identified with these methods were experimentally validated. This approach has practical implications for understanding the impact of host immunity on pathogen evolution and for defining relevant variants for inclusion in vaccine antigens.
NextPage
1 Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
2 Santa Fe Institute, Santa Fe, NM 87501, USA.
3 Machine Learning and Applied Statistics Group, Microsoft Research, Redmond, WA 98052, USA.
4 Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
5 Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA.
6 Center for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia.
7 Department of Microbiology, University of Washington, Seattle, WA 98195–8070, USA.
8 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
* To whom correspondence should be addressed. E-mail: btk@lanl.gov
原文二：
--------------------------------------------------------------------------------
Science 16 March 2007:
Vol. 315. no. 5818, pp. 1583 - 1586
DOI: 10.1126/science.1131528
Founder Effects in the Assessment of HIV Polymorphisms and HLA Allele Associations
Tanmoy Bhattacharya,1,2 Marcus Daniels,1 David Heckerman,3 Brian Foley,1 Nicole Frahm,4 Carl Kadie,3 Jonathan Carlson,3,5 Karina Yusim,1 Ben McMahon,1 Brian Gaschen,1 Simon Mallal,6 James I. Mullins,7 David C. Nickle,7 Joshua Herbeck,7 Christine Rousseau,7 Gerald H. Learn,7 Toshiyuki Miura,4 Christian Brander,4 Bruce Walker,4,8 Bette Korber1,2*
Escape from T cell–mediated immune responses affects the ongoing evolution of rapidly evolving viruses such as HIV. By applying statistical approaches that account for phylogenetic relationships among viral sequences, we show that viral lineage effects rather than immune escape often explain apparent human leukocyte antigen (HLA)–mediated immune-escape mutations defined by older analysis methods. Phylogenetically informed methods identified immune-susceptible locations with greatly improved accuracy, and the associations we identified with these methods were experimentally validated. This approach has practical implications for understanding the impact of host immunity on pathogen evolution and for defining relevant variants for inclusion in vaccine antigens.
1 Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
2 Santa Fe Institute, Santa Fe, NM 87501, USA.
3 Machine Learning and Applied Statistics Group, Microsoft Research, Redmond, WA 98052, USA.
4 Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
5 Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA.
6 Center for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia.
7 Department of Microbiology, University of Washington, Seattle, WA 98195–8070, USA.
8 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
* To whom correspondence should be addressed. E-mail: btk@lanl.gov
