生物谷:美国科学家在7月19日的《科学》在线版上发表论文称,他们初步揭示了为什么有些人能更好地抵抗艾滋病毒(HIV)。这将有助于开发出抗艾药新的药靶。
HIV感染人体后,其破坏人体免疫系统的速度决定于人体的最初反应。乍一感染,HIV水平会急速上升,但是很快人体免疫系统和细胞产生的其它抗病毒因子就会使血液中的HIV水平下降,并建立一个“临界点”(set point)。临界点越低,免疫系统有效抵御病毒的时间就会越长。
为了弄清其中的机制,由美国杜克大学遗传学家David Goldstein领导的小组对此进行了研究。他们研究了486位感染HIV的患者,这些患者的感染时间和临界点均很清楚,并且尚未接受任何治疗。研究人员核对了来自DNA序列或单核苷酸多态性(single-nucleotide polymorphisms,简称SNP)的已知50万种变化。他们发现有两种多态性能说明病毒临界点中15%的变化。这两种多态性的作用彼此互不相干,但是均与临界点的降低有关。
其中一种多态性作用较强,发生在含有HCP5基因(该基因编码一种人体内生型逆转录酶病毒)的DNA片断或多态性中。研究人员发现体内含有该种多态性的患者往往还具有一种稀有基因,该基因名为HLA-B*5701,能够通过清除体内感染HIV细胞强力抵抗HIV。另外一种多态性存在于HLA-C基因中,该基因在促进免疫系统有效运作方面与HLA-B作用类似。研究人员表示,关于这两种多态性降低病毒临界点的机制,目前尚不清楚。一旦弄清,将会有助于开发出抗艾药新的药靶及新疫苗。
美国西北大学艾滋病研究人员Steven Wolinsky认为,该项研究很令人激动,但是主要关注的是白种人。如果研究对象的遗传背景能够更广阔一些,那么将会更加令人信服。(科学网 梅进/编译)
原始出处:
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Published Online July 19, 2007
Science DOI: 10.1126/science.1143767
Reports
Submitted on April 13, 2007
Accepted on July 3, 2007
A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1
Jacques Fellay 1, Kevin V. Shianna 2, Dongliang Ge 1, Sara Colombo 3, Bruno Ledergerber 4, Mike Weale 1, Kunlin Zhang 3, Curtis Gumbs 1, Antonella Castagna 5, Andrea Cossarizza 6, Alessandro Cozzi-Lepri 7, Andrea De Luca 8, Philippa Easterbrook 9, Patrick Francioli 10, Simon Mallal 11, Javier Martinez-Picado 12, José M. Miro 13, Niels Obel 14, Jason P. Smith 2, Josiane Wyniger 3, Patrick Descombes 15, Stylianos E. Antonarakis 16, Norman L. Letvin 17, Andrew J. McMichael 18, Barton F. Haynes 19, Amalio Telenti 3*, David B. Goldstein 1*
1 Center for Population Genomics and Pharmacogenetics, Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
2 Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
3 Institute of Microbiology, University Hospital Center and University of Lausanne, 1011 Lausanne, Switzerland.
4 Division of Infectious Diseases, University Hospital, 8091 Zürich, Switzerland.
5 Clinic of Infectious Diseases, IRCCS San Raffaele Hospital, 20127 Milan, Italy.
6 Department of Biomedical Sciences, Section of General Pathology, University of Modena and Reggio Emilia, School of Medicine, 41100 Modena, Italy.
7 Department of Primary Care and Population Sciences, Royal Free and University College Medical School, UCL London NW3 2PF, UK.
8 Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, 00168 Rome, Italy.
9 Academic Department of HIV/GUM, Kings College London, at Guy's, King's, and St Thomas' Hospitals, London SE5 9RJ, UK.
10 Service of Infectious Diseases, Department of Medicine and Service of Hospital Preventive Medicine, University Hospital Center, 1011 Lausanne, Switzerland.
11 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, WA 6000, Australia.
12 irsiCaixa Foundation and Hospital Germans Trias i Pujol, 08916 Badalona, Spain, and Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
13 Hospital Clinic - IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
14 Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.
15 Genomics Platform, NCCR "Frontiers in Genetics," University of Geneva, 1211 Geneva, Switzerland.
16 Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
17 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
18 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
19 Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA.
* To whom correspondence should be addressed.
Amalio Telenti , E-mail: amalio.telenti@chuv.ch
David B. Goldstein , E-mail: d.goldstein@duke.edu
Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701, while a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated a third locus encoding a RNA polymerase subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.