The global spread of hepatitis C virus 1a and 1b: a phylodynamic and phylogeographic analysis.
The global spread of hepatitis C virus 1a and 1b: a phylodynamic and phylogeographic analysis.
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DOI：
10.1371/journal.pmed.1000198
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发表时间：
2009-12
期刊：
影响因子：
15.8
通讯作者：
Hatzakis A
中科院分区：
文献类型：
--
作者：
Magiorkinis G;Magiorkinis E;Paraskevis D;Ho SY;Shapiro B;Pybus OG;Allain JP;Hatzakis A
利用系统动力学和系统地理学方法，Angelos Hatzakis及其同事发现，丙型肝炎病毒的全球传播与输血的广泛使用和静脉注射药物的扩大同时发生。据估计，全世界有1.3亿至1.8亿人感染丙型肝炎病毒。虽然其起源不明，但病毒多样性模式提示HCV基因1型可能起源于西非。以前对该病毒在全球和区域的时空参数进行估计的尝试表明，HCV的流行传播始于1900年，并在20世纪80年代末之前稳步增长。然而，流行病学数据表明，丙型肝炎病毒的扩大可能发生在第二次世界大战后。我们研究的目的是阐明HCV全球传播的时间尺度和途径。我们发现很少测序的HCV区域（E2P7NS2）比更常用的NS5B区域更能提供分子流行病学研究的信息。我们将系统动力学方法应用于大量新的E2P7NS2和NS5B序列，以及所有可用的具有这两个基因组区域信息的全球HCV序列，以估计最流行的HCV亚型1a和1b的全球扩展的时间尺度和性质。我们发现，在1940年至1980年间，1a和1b亚型的传播呈“爆炸式”增长，其中1b的传播比1a的传播至少早16年（95%置信区间15-17）。所有可用的NS5B序列的系统地理分析表明，HCV亚型1a和1b是从发达国家传播到发展中国家的。HCV的进化速度似乎比以前认为的要快。丙型肝炎病毒的全球传播与输血和血液制品的广泛使用以及静脉注射药物使用的扩大同时发生，但在广泛实施抗丙型肝炎病毒筛查之前，传播速度有所减缓。与1a和1b亚型相关的传播途径的差异为1b相对较早的扩展提供了解释。我们的数据显示，HCV传播最合理的途径是从发达国家到发展中国家。约有1.5亿人（占世界人口的3%）长期（慢性）感染丙型肝炎病毒（HCV），每年约有300万至400万人感染这种病毒。hcv是慢性肝炎（肝脏炎症）的主要原因，通过接触受感染的血液传播。传播途径包括医疗程序（例如，输入未经筛选的血液）和静脉注射吸毒者共用针头。这第二种传播途径在发达国家最为常见，在这些国家，血液在用于输血之前通常要经过筛查。丙型肝炎病毒感染可引起以疲劳和黄疸（皮肤和眼睛发黄）为特征的短期疾病，但大多数新感染者进展为无症状的慢性感染，最终可导致肝硬化（瘢痕形成）和肝癌。丙型肝炎病毒感染可以用干扰素和利巴韦林两种昂贵的药物联合治疗，但这两种药物对许多患者无效。没有人确切知道丙型肝炎病毒的起源，尽管有证据表明它首先出现在西非或东南亚。目前也不清楚丙型肝炎病毒的流行是何时开始的。在本研究中，研究人员试图通过分析不同时间和地点采集的HCV样本的基因组序列来阐明HCV全球传播的时间尺度和途径。HCV是一种核糖核酸（RNA）病毒。也就是说，它储存了复制自身所需的信息——它的基因组——作为一系列“核糖核苷酸”。像其他RNA病毒一样，HCV基因组不断积累微小的变化（突变），随着时间的推移，HCV进化成几种不同的“基因型”，每种基因型都有几个不同的亚型。此外，同一亚型的病毒有细微的基因组差异。通过使用复杂的“系统动力学”和“系统地理学”方法分析这种病毒多样性，科学家可以建立一幅关于丙型肝炎病毒如何在人群中进化以及它如何传播到目前的地理分布的图景。通过检查1994年至2006年在雅典大学医学院（希腊）收集的HCV样本的基因组，研究人员首先定义了一个名为E2P7NS2的HCV可变区域，该区域比以前研究中使用的NS5B区域更能提供系统动力学研究的信息。然后，他们检索了过去20-30年在洛斯阿拉莫斯HCV序列数据库中收集的1a和1b亚型样本的两个区域的序列；丙型肝炎病毒亚型1a和1b占全球丙型肝炎病毒感染的60%。研究人员对这些全球代表性序列（收集于美国、德国、瑞士和希腊）的系统动力学分析表明，从1906年到20世纪60年代，HCV亚型1a的传播率很低，而在此期间，其传播率呈爆炸式增长。同样，从1922年到20世纪40年代末，1b亚型的传播率很低，但随后呈指数增长。从1980年起，这两种亚型的流行率稳定在较高水平。研究人员的系统地理学分析（分别考虑了在21个国家和29个国家收集的1a和1b NS5B序列）表明，HCV亚型1a和1b可能已经从发达国家传播到发展中国家。这些发现表明，乙型丙型肝炎病毒的流行始于20世纪40年代，当时输血和血液制品的使用变得广泛，而甲型丙型肝炎病毒流行的开始与20世纪60年代注射药物使用的扩大相吻合。研究结果还表明，在20世纪90年代早期广泛实施HCV筛查之前，两种亚型的传播率可能已经放缓，可能是因为当时医学界已经意识到与血液污染相关的一般风险。最后，这些发现为丙型肝炎病毒如何在世界范围内传播提供了新的见解，并表明丙型肝炎病毒的进化速度可能比以前认为的要快。然而，由于这项研究依赖于短时间内收集的少量样本，因此其发现需要在更大规模的研究中得到证实。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.1000198访问这些网站。世界卫生组织提供丙型肝炎和丙型肝炎的详细信息，美国疾病控制和预防中心为公众和卫生专业人员提供丙型肝炎的信息（也有西班牙语版），美国国家糖尿病、消化和肾脏疾病研究所提供丙型肝炎的基本信息（英语和西班牙语版），MedlinePlus提供更多丙型肝炎资源的链接，洛斯阿拉莫斯HCV数据库是美国国家生物技术信息中心提供了一本关于科学家如何从序列信息重建进化途径的科学入门书
Using phylodynamic and phylogeographic methods, Angelos Hatzakis and colleagues find that the global spread of Hepatitis C virus coincided with widespread use of transfused blood and with the expansion of intravenous drug use. Hepatitis C virus (HCV) is estimated to affect 130–180 million people worldwide. Although its origin is unknown, patterns of viral diversity suggest that HCV genotype 1 probably originated from West Africa. Previous attempts to estimate the spatiotemporal parameters of the virus, both globally and regionally, have suggested that epidemic HCV transmission began in 1900 and grew steadily until the late 1980s. However, epidemiological data suggest that the expansion of HCV may have occurred after the Second World War. The aim of our study was to elucidate the timescale and route of the global spread of HCV. We show that the rarely sequenced HCV region (E2P7NS2) is more informative for molecular epidemiology studies than the more commonly used NS5B region. We applied phylodynamic methods to a substantial set of new E2P7NS2 and NS5B sequences, together with all available global HCV sequences with information in both of these genomic regions, in order to estimate the timescale and nature of the global expansion of the most prevalent HCV subtypes, 1a and 1b. We showed that transmission of subtypes 1a and 1b “exploded” between 1940 and 1980, with the spread of 1b preceding that of 1a by at least 16 y (95% confidence interval 15–17). Phylogeographic analysis of all available NS5B sequences suggests that HCV subtypes 1a and 1b disseminated from the developed world to the developing countries. The evolutionary rate of HCV appears faster than previously suggested. The global spread of HCV coincided with the widespread use of transfused blood and blood products and with the expansion of intravenous drug use but slowed prior to the wide implementation of anti-HCV screening. Differences in the transmission routes associated with subtypes 1a and 1b provide an explanation of the relatively earlier expansion of 1b. Our data show that the most plausible route of the HCV dispersal was from developed countries to the developing world. Please see later in the article for the Editors' Summary About 150 million people (3% of the world's population) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people become infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with infected blood. Transmission routes include medical procedures (for example, transfusions with unscreened blood) and needle-sharing among intravenous drug users. This second transmission route is the most common one in developed countries where blood is now routinely screened before being used in transfusions. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes), but most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two expensive drugs called interferon and ribavirin, but these drugs are ineffective in many patients. Noone knows for sure where HCV originated although there is some evidence that it appeared first in West Africa or Southeast Asia. It is also unclear when the current HCV epidemic began. In this study, the researchers try to elucidate both the timescale and route of the global spread of the HCV epidemic by analyzing the genome sequence of HCV samples collected at different times and places. HCV is a ribonucleic acid (RNA) virus. That is, it stores the information it needs to replicate itself—its genome—as a series of “ribonucleotides.” Like other RNA viruses, the HCV genome continually accumulates small changes (mutations) and, over time, HCV has evolved into several different “genotypes,” each of which has several distinct subtypes. Furthermore, the viruses within a single subtype have subtly different genomes. By analyzing this viral diversity using complex “phylodynamic” and “phylogeographic” methods, scientists can build up a picture of how HCV has evolved in populations and how it has spread to reach its current geographical distribution. By examining the genomes of HCV samples collected between 1994 and 2006 at the Athens University Medical School (Greece), the researchers first defined a variable region of HCV called E2P7NS2 that is more informative for phylodynamic studies than the NS5B region that has been used in previous studies. They then retrieved the sequences of both regions for subtype 1a and 1b samples collected over the past 20–30 years in the Los Alamos HCV sequence database; HCV subtypes 1a and 1b cause 60% of global HCV infections. The researchers' phylodynamic analyses of these globally representative sequences (collected in the USA, Germany, Switzerland, and Greece) indicate that the transmission of HCV subtype 1a occurred at a low rate from 1906 until the 1960s, at which time there was an explosive increase in its transmission rate. Similarly, subtype 1b transmission occurred at a low rate from 1922 until the late 1940s but then increased exponentially. From 1980 onwards, the prevalence of both subtypes stabilized at a high level. The researchers' phylogeographic analyses (which considered 1a and1b NS5B sequences collected in 21 and 29 countries, respectively) suggest that HCV subtypes 1a and 1b may have spread from the developed to the developing world. These findings indicate that the epidemic of HCV subtype 1b began in the 1940s when the use of transfused blood and blood products became widespread whereas the start of the subtype 1a epidemic coincided with the expansion of injected drug use that occurred in the 1960s. The findings also suggest that the transmission rates of both subtypes may have slowed before the widespread implementation of HCV screening in the early 1990s, possibly because the medical community was aware by then of the general risks associated with blood contamination. Finally, these findings provide new insights into how the HCV epidemic spread around the world and suggest that HCV may be evolving faster than previously thought. However, because this study relied on a small number of samples collected over a short time period, its findings need to be confirmed in larger studies. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000198. The World Health Organization provides detailed information about hepatitis C and HCV The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish) The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish) MedlinePlus provides links to further resources on hepatitis C The Los Alamos HCV database is available The US National Center for Biotechnology Information provides a science primer on how scientists reconstruct evolutionary pathways from sequence information
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影响因子：
9.8
作者：
Drummond AJ;Ho SY;Phillips MJ;Rambaut A
通讯作者：
Rambaut A
影响因子：
56.9
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Korber, B;Muldoon, M;Bhattacharya, T
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DOI：
10.1073/pnas.0705329104
发表时间：
2007-11-20
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
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影响因子：
10.7
作者：
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