在每一位感染患者的T細(xì)胞和人類免疫缺陷病毒間的艱難博弈中,，互相間的規(guī)則總是變幻無(wú)常。T細(xì)胞采用持續(xù)識(shí)別HIV蛋白的策略使免疫系統(tǒng)處于警覺(jué)狀態(tài)對(duì)HIV發(fā)動(dòng)攻擊,。但是病毒卻是“野火燒不盡,，春風(fēng)吹又生”，因?yàn)镠IV的突變體能逃脫免疫監(jiān)視,。
因?yàn)槿梭w免疫系統(tǒng)不能對(duì)付HIV,，免疫逃避致使該病毒具有更大的危險(xiǎn)性。當(dāng)研究人員致力于發(fā)展一種協(xié)助免疫系統(tǒng)對(duì)付HIV的疫苗時(shí),，他們希望準(zhǔn)確知道是哪種突變使 HIV逃避清除的,。
研究人員最初相信，通過(guò)對(duì)HIV突變橫斷面分析,，他們能限定這些最終導(dǎo)致免疫逃避的突變,，而且能精確找到病毒基因組中對(duì)于T細(xì)胞識(shí)別重要的序列。
霍華德-休斯醫(yī)學(xué)研究所研究員布魯斯-沃克參與的一個(gè)科學(xué)家團(tuán)隊(duì)研究確認(rèn),，由于在整個(gè)循環(huán)中HIV亞型眾多,，因此該分析的準(zhǔn)確性受到影響。這是因?yàn)槠渲幸恍┩蛔兇砹艘酝l(fā)展而來(lái)的亞型或家族血緣差異,，而不是作為免疫選擇壓力結(jié)果而產(chǎn)生的突變,。沃克和同事們發(fā)現(xiàn)對(duì)這些HIV多家族性突變存在的鑒別可以在很大程度上提高遺傳分析的準(zhǔn)確性。進(jìn)而,，在病毒基因組序列間闡明多種發(fā)生關(guān)系的統(tǒng)計(jì)學(xué)方法將給病毒學(xué)家對(duì)病毒進(jìn)化提供新的視角,，以及病毒如何通過(guò)改變自身突變適應(yīng)人體免疫系統(tǒng)。研究人員在2007年3月16日《科學(xué)》雜志上發(fā)表了他們的新方法,。
科伯說(shuō)：“這是一個(gè)開(kāi)創(chuàng)性研究,，因?yàn)樵撗芯匡@示在人類免疫系統(tǒng)的生物學(xué)影響下這些免疫基因HIV是如何進(jìn)化的。但是使用該方法沒(méi)有考慮不同病毒品系共存的可能性,，而這可能對(duì)分析有影響,。”沃克稱，HIV疫苗設(shè)計(jì)的挑戰(zhàn)在于確定病毒逃避清除的準(zhǔn)確突變方式,，但是現(xiàn)有的方法不能區(qū)分來(lái)自實(shí)際免疫逃避和由歷史發(fā)展分化而來(lái)的HIV亞型,。
在新研究中，科伯,、沃克和他們的同事使用新的統(tǒng)計(jì)手段對(duì)來(lái)自珀斯的資料重新分析,，可以追蹤個(gè)體患者體內(nèi)有多少病毒遺傳亞型?？撇Q,，將這些族譜效應(yīng)考慮進(jìn)去，導(dǎo)致“與最初文獻(xiàn)報(bào)告相比，免疫選擇的特殊本質(zhì)特征有非常大的差異,。”研究人員著重研究了兩種HIV蛋白的病毒基因,。這些實(shí)驗(yàn)出現(xiàn)的遺傳特征顯示，先前認(rèn)為是來(lái)自同族的HIV樣本實(shí)際上包含一個(gè)以上HIV遺傳亞型,。沃克和科伯稱,，多HIV亞型的存在削弱了遺傳分析的準(zhǔn)確性。甚至在這些亞型中,，研究人員發(fā)現(xiàn)遺傳學(xué)上不同的“亞系”將導(dǎo)致免疫逃避遺傳學(xué)分析的準(zhǔn)確性進(jìn)一步降低,。他們說(shuō)，這種新方法考慮到多種系發(fā)生的關(guān)系將提高未來(lái)分析的準(zhǔn)確性,。沃克說(shuō)：“這些新生物信息學(xué)技術(shù),，結(jié)合流行病擴(kuò)充實(shí)時(shí)產(chǎn)生的功能免疫資料，對(duì)具有非常大變異性能力的HIV疫苗設(shè)計(jì)至關(guān)重要,。”“該方法普遍適用其他病毒和其他HIV研究,，”科伯說(shuō)，“例如,，同事和我正使用這種方法探詢?cè)趥魅緯r(shí),，與慢性感染中存在的病毒相比，傳染的HIV是否有遺傳差異,。所有這類信息將幫助疫苗設(shè)計(jì)者作出合理決策,，產(chǎn)生最大人口覆蓋的疫苗應(yīng)該包括哪些遺傳成分。”
科伯說(shuō),，該新分析法還指出相同的HIV遺傳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則易被清除。她說(shuō),，這樣的觀點(diǎn)對(duì)疫苗形成非常重要,，這種疫苗具有充分變異，能在大多數(shù)身上起最大效應(yīng),。沃克說(shuō)：“該項(xiàng)目是來(lái)自多領(lǐng)域科學(xué)家共同努力的絕佳例證,，為正在全球泛濫的AIDS提供了全新認(rèn)識(shí)。”科伯和她的同事正運(yùn)用他們的方法分析HIV基因組中所有產(chǎn)生蛋白的基因,，在《科學(xué)》雜志發(fā)表的兩個(gè)報(bào)道外,，進(jìn)一步獲得對(duì)免疫逃避機(jī)制的認(rèn)識(shí)。
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: [email protected]
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: [email protected]
