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类型 综合研究 预答辩日期 2017-12-21
开始(开题)日期 2016-11-04 论文结束日期 2017-11-04
地点 东南大学丁家桥校区公卫楼3楼会议室 论文选题来源 教育部人文、社会科学研究项目     论文字数 6.8 (万字)
题目 青年学生HIV/AIDS流行特征及HIV-1分子传播网络研究
主题词 青年学生,I型人类免疫缺陷病毒,男男性行为人群,系统进化分析,分子传播网络
摘要 研究背景与目的 近年来,我国青年学生中HIV/AIDS疫情呈上升态势,其中超过80%的感染者为男男性行为人群(MSM)。尽管目前已开展了较多关于青年学生MSM的调查,但青年学生艾滋病病毒感染者/艾滋病患者(PLWH)的相关“知识-态度-行为”(KAP)现状、HIV-1分子流行病学特征及传播网络特征还并不清楚。据此,本课题以南京地区确诊的青年学生PLWH为研究对象,开展现场流行病学及HIV-1分子流行病学相结合的专题研究,为制定控制HIV/AIDS在该人群中快速蔓延的措施提供依据。 研究方法 1. 招募2015年10月-2017年6月期间在南京地区新诊断的155例青年学生PLWH及425例非学生PLWH。以问卷调查方式收集艾滋相关“KAP”信息。通过分析其中152例男性学生的基本人口学资料、艾滋相关“KAP”现状、抗病毒治疗情况及患性病情况,了解青年学生MSM的HIV/AIDS特征。 2. 通过HIV-1核酸提取和聚合酶链反应(PCR)扩增Pol区基因片段,开展HIV-1分子流行病学研究。以邻接法构建进化树对HIV-1进行基因分型,新型重组毒株以Simplot3.5.1软件探索重组模式。使用斯坦福大学HIV耐药数据库在线工具HIVdb Program检测耐药突变位点。加入相关参考序列后,构建最大似然树描述不同亚型毒株在学生人群中的流行现状。基于贝叶斯系统进化分析推断青年学生中各亚型毒株的地理来源;并以贝叶斯合意模型Skyline plot模拟新型重组毒株的流行趋势。 3. 通过构建进化树、提取传播簇、选择最小基因距离及可视化传播网络4个步骤构建CRF01_AE及CRF07_BC两个优势毒株的分子传播网络。传播簇判定标准为树节点值≥95%且簇内最大基因距离≤0.03。以最小共祖基因距离准则界定簇内个体之间的关联。描述性分析学生人群中病毒的人群来源及地区来源,并鉴定网络内超级传播者的特征。通过卡方检验分析影响网络形成及感染者成为超级传播者的因素。 主要研究结果 1. 男大学生PLWH艾滋相关“KAP”现状。男大学生PLWH中,男男同性传播途径占96.1%(146/152),52.6%(80/152)为大二及以下年级。男大学生PLWH对新“国八条”的总体知晓率为86.2%(131/152),其中条目6和条目2的知晓率最低,分别为65.8%(100/152)和70.4%(107/152);对男性固定性伴、男性偶然性伴、女性固定性伴及女性偶然性伴感染状况知晓的比例分别为16.4%(18/110)、3.0%(3/101)、50.0%(11/22)和16.7%(2/12),与上述性对象发生性行为时能意识到可能被感染疾病的比例分别为20.9%(23/110)、27.7%(28/101)、0.0%(0/22)和16.7%(2/12),与上述性对象发生性行为能够坚持一直使用安全套的比例分别为10.9%(12/110)、11.9%(12/101)、18.2%(4/22)和33.3%(4/12);此外,通过手机APP联络上述性伴的比例分别为84.2%(84/99)、92.6%(88/95)、19.0%(4/21)和30%(3/10)。 2. 男大学生PLWH诊断治疗状况。确诊后首次随访CD4计数中位水平为417.0(IQR:319.0-527.0)cells/μL,其中≥500cells/μL的比例占31.5%(47/149)。至统计截止日期(2017年7月1日)时,开始抗病毒治疗的比例为69.7%(106/152),从确诊到开始治疗的中位时间间隔为45.5(IQR:28.0-130.5)天;46例未进行抗病毒治疗者从确诊到统计截止日期的中位时间间隔为494.5(IQR:275.0-1195.0)天。 3. HIV-1基因型在青年学生中的分布。共141例学生PLWH的Pol区被成功扩增。HIV-1基因型以CRF01_AE和CRF07_BC为主,分别占46.1%(65/141)和32.6%(46/141),其次依次为CRF55_01B(3.5%,5/141)、CRF67_01B(3.5%,5/141)、B亚型(2.1%,3/141)及CRF68_01B(0.7%,1/141),此外还有11.3%(16/141)的未鉴定U亚型。其基因型的整体分布情况与非学生人群较为相似。 4. HIV-1在青年学生中的流行特征。不同基因型的HIV-1毒株在学生人群中具有各自的流行特征。CRF01_AE中,92.3%(60/65)的学生位于4个大流行枝内,其中一半(52.3%,34/65)的学生处于流行枝1内。而CRF07_BC中,大部分学生序列(71.7%,33/46)分散在多个小流行枝内。16条未鉴定的U亚型序列中,以01C_like重组模式为主(81.3%,13/16),且已形成了一个明显的01C_like南京流行簇在学生人群中急剧传播。 5. HIV-1传播网络特征及影响因素。通过HIV-1分子传播网络分析,共形成CRF01_AE学生相关网络23个,包括了49.2%(32/65)的学生序列;形成CRF07_BC学生相关网络22个,包括了63.0%(29/46)的学生序列。较低的诊断年龄(P=0.041)、男男性行为感染途径(P=0.020)、新近感染(P<0.001)及较低的安全套使用率(P<0.05)为促进网络形成的因素。 6. “超级传播者”特征及影响因素。CRF01_AE学生相关网络的103条序列中,links≥3的占12.6%(13/103),但与47.6%(49/103)的网络内序列相关,其中有6个“超级传播者”分别关联了6个学生。CRF07_BC学生相关网络的112条序列中,links≥3的占8.3%(16/112),与51.8%(58/112)的网络内序列相关,其中有7个“超级传播者”分别关联了7个学生。男男性行为感染途径(P=0.024)、新近感染(P=0.001)及较低的安全套使用率(P<0.001)为促进感染者成为超级传播者的因素。 7. 青年学生中HIV-1病毒的人群来源及地区来源。CRF01_AE网络内的32个学生感染者中,71.9%(23/32)来自非学生人群的传播,18.7%(6/32)来自学生人群;50%(16/32)来自南京地区,9.4%(3/32)来自省内其他市,25%(8/32)来自外省。CRF07_BC网络内的29个学生感染者中,93.2%(27/29)来自非学生人群的传播,3.4%(1/29)来自学生人群;31.0%(9/29)来自南京,6.9%(2/29)来自省内其他市,24.1%(7/29)来自外省。 研究结论 1. 青年学生MSM人群HIV-1感染逐趋低龄化,防艾教育的开展应注重早期性、及时性和全程性。该人群艾滋相关“KAP”现状不容乐观,应深化开展高校防艾风险警示教育,使其知晓高校疫情、增强防艾意识,切实提高安全套使用率。手机APP已成为该群体联络性伴的主要工具,应充分发挥其在艾滋病防控中的作用。未被早期诊断及未及时开展抗病毒治疗者仍具有较高比例,表明动员检测工作还有待进一步加强,普及抗病毒治疗知识力度仍需加大,且应动员长期未治疗的PLWH尽早开始抗病毒治疗。 2. CRF_5501B、CRF_6701B及CRF_6801B等多种新型重组毒株在南京地区广泛流行,且已进入学生人群;未被鉴定的01C_like毒株在学生人群中急剧传播。需密切监测这些毒株的流行态势并制定有效防控措施,阻止其在学生人群中的进一步蔓延。 3. 南京地区青年学生MSM感染的病毒主要来源于非学生人群,并与多个省外城市之间关联紧密,反映了该人群中病毒来源的复杂性,也强调了高校防艾应纳入全人群防艾整体布局的重要性。 4. 网络内的少数“超级传播者”促进了病毒的扩散,鉴定和精准干预这些核心人群对控制HIV-1在全人群中的传播具有重要作用。男男性行为、早期感染及较低的安全套使用率为促进网络形成和感染者成为超级传播者的主要因素。因此,需继续深化控制MSM人群中的HIV-1疫情,进一步开展检测和抗病毒治疗动员工作,并大力开展安全套推广策略行动,提高安全套的可及性和使用率。
英文题目 The Epidemiological Characteristics of HIV/AIDS and the Transmission Networks of HIV-1 among Young Students
英文主题词 Young students;HIV-1;MSM;Phylogenetic analysis;Genetic transmission networks
英文摘要 Objectives In recent years, the epidemic of HIV/AIDS among young students has been increasing rapidly in China, especially in men who have sex with men (MSM). Although many surveys have been conducted for presenting the characteristics of MSM in young students, the status of AIDS-related knowledge, attitude and practices (KAP), the molecular epidemiological characteristics of HIV-1 and the feature of transmission networks were still largely unknown among people living with HIV/AIDS (PLWH) in young students. In the present study, we combined analysis of genetic, demographic and epidemiological data of HIV-1 among young students in Nanjing, aiming to provide valuable information for taking effective prevention measures against HIV-1 transmission. Methods 1. A total of 155 young students and 425 non-students were recruited at the first follow-up after HIV-1 diagnosis in Nanjing during 10/2015-06/2017. The information of AIDS-related KAP was collected by questionnaires. The data about social demography, AIDS-related KAP, Highly Active Antiretroviral Therapy (HAART) and sexually transmitted diseases (STDs) of 152 male students were analyzed, in order to understand the HIV/AIDS characteristics of MSM in young students. 2. The Pol sequences were acquired after RNA extraction and PCR amplification. A Neighbor-Joining tree was constructed to determine HIV-1 genotypes. The unidentified genotypes were analyzed with Simplot3.5.1 software. HIV-1 Drug resistance mutations were determined using Stanford University HIV Drug Resistance Database tool: HIVdb Program. The epidemiological characteristics of various strains in young students were described by reconstructing the maximum likelihood trees with reference sequences. The geographical origin of each strain in young students was inferred by the Bayesian evolutionary analysis. The changes in the effective population size of the new recombinant strains were explored by the Bayesian skyline plot analysis. 3. The genetic transmission networks of CRF01_AE and CRF07_BC strains were constructed by four steps, including phylogenetic tree construction, transmission cluster extraction, minimum genetic distance identification and network visualization. Cluster Picker was used to extract transmission clusters from the phylogenetic tree, with the node support threshold greater than 95% and intra-cluster maximum pairwise distance less than 3.0% nt substitutions per site. The minimum patristic genetic distance algorithm was used to define the linkages within a cluster. Descriptive analysis was used for exploring the population and geographic origin of HIV-1 in students, and for identifying the characteristics of super-spreaders in the networks. Chi-square test was used to determine the factors that contributed to the networks and super-spreaders. Results 1. HIV-related KAP of PLWH among male college students. Among PLWH in male college students, 96.1% (146/152) were infected by homosexual behaviors, and 52.6% (80/152) were freshman and sophomore. The overall awareness rate of ‘Eight Items of HIV/AIDS Knowledge’ was 86.2% (131/152), with the awareness rates of item 6 (65.8%, 100/152) and 2 (70.4%, 107/152) lower than those of the other six items. The awareness rates of the infected status towards male regular sexual partners, male casual sexual partners, female regular sexual partners and female casual sexual partners were 16.4% (18/110), 3.0% (3/101), 50.0% (11/22) and 16.7% (2/12), respectively. While having sex with those sexual partners, the proportions of male college students having the awareness that they may be infected with diseases were 20.9% (23/110), 27.7% (28/101), 0.0% (0/22) and 16.7% (2/12), respectively, and the proportions of using condoms insistently were 10.9% (12/110), 11.9% (12/101), 18.2% (4/22) and 33.3% (4/12), respectively. In addition, the proportions of individuals who contact those sexual partners by mobile applications were 84.2% (84/99), 92.6% (88/95), 19.0% (4/21) and 30% (3/10), respectively. 2. The status of diagnosis and treatment of PLWH among male college students. The median CD4+T cell count of the first follow-up after diagnosis was 417.0 (IQR: 319.0-527.0) cells/μL, and 31.5% (47/149) individuals had CD4+T cell count ≥500 cells/μL. The rate of the PLWH having accepted HAART was 69.7% (106/152) until deadline (July 1, 2017). The median of interval time from diagnosis to HAART was 45.5 (IQR: 28.0-130.5) days. For the 46 PLWH who did not start treatment, the median of interval time from diagnosis to deadline was 494.5 (IQR: 275.0-1195.0) days. 3. The distribution of HIV-1 genotypes among young students. A total of 141 Pol sequences among students were amplified successfully. CRF01_AE was the most prevalent strains, accounting for 46.1% (65/141), followed by CRF07_BC (32.6%, 46/141), CRF55_01B (3.5%, 5/141), CRF67_01B (3.5%, 5/141), subtype B (2.1%, 3/141) and CRF68_01B (0.7%, 1/141). In addition, 11.3% (16/141) of sequences were the unidentified genotypes (U). The overall distribution of HIV-1 genotypes among young students was similar to that among non-students. 4. The epidemiological characteristics of HIV-1 among young students. Different HIV-1 strains had various epidemiological characteristics among students. Above 90.0% (60/65) of students were located in four major lineages of CRF01_AE strains, and nearly half of (52.3%, 34/65) students were located in lineage 1, while 71.7% (33/46) of students were dispersed in multiple minor lineages of CRF07_BC strains. In addition, the majority of 16 unidentified genotype U sequences were 01C_like recombinants (81.3%, 13/16), which had formed a distinct cluster spreading rapidly among young students in Nanjing. 5. Characteristics and influencing factors of HIV-1 transmission networks. Of the 65 CRF01_AE sequences, 32 (49.2%) were identified as belonging to 23 separated networks. Of the 46 CRF07_BC sequences, 29 (63.0%) were identified as belonging to 22 separated networks. Lower age while being diagnosed (P=0.041), homosexual behaviors (P=0.020), recent infection (P<0.001) and a lower rate of condom usage (P<0.05) were factors of contributing to network formation. 6. Characteristics and influencing factors of super-spreaders. Of 103 CRF01_AE-infected individuals in student-related networks, 12.6% (13/103) had ≥3 links, but they were involved in 47.6% (49/103) persons through multiple links. Among 13 CRF01_AE-infected super-spreaders, 6 individuals shared links with 6 students respectively. Of 112 CRF07_BC-infected individuals in student-related networks, 8.3% (16/112) had ≥3 links, but they were involved in 51.8% (58/112) persons through multiple links. Among 16 CRF07_BC-infected super-spreaders, 7 individuals shared links with 7 students respectively. Homosexual behaviors (P=0.024), recent infection (P=0.001) and a lower rate of condom usage (P<0.001) were factors associated with super-spreaders. 7. Population and geographical origin of HIV-1 among young students. Of 32 students in CRF01_AE networks, 71.9% (23/32) were infected by non-students, and 18.7% (6/32) were infected by students. Among the 32 CRF01_AE-infected students, half of (50.0%, 16/32) persons had transmission linkage with individuals diagnosed in Nanjing. In addition, 9.4% (3/32) and 25.0% (8/32) of persons had transmission linkage with individuals diagnosed in other cities in Jiangsu province and other provinces, respectively. Of 29 students in CRF07_BC networks, 93.2% (27/29) were infected by non-students, and 3.4% (1/29) were infected by students. Among the 29 CRF07_BC-infected students, 31.0% (9/29) and 6.9% (2/29) persons had transmission linkage with individuals diagnosed in Nanjing and other cities in Jiangsu province, respectively. In addition, 24.1% (7/29) of persons had transmission linkage with individuals diagnosed in other provinces. Conclusions 1. The age of infecting with HIV-1 becomes younger, thus the AIDS prevention education should be carried early, timely and comprehensively. As the HIV-related KAP of young students is unpromising, it is necessary to strengthen risk warning education to increase AIDS knowledge rate, to enhance the awareness of AIDS prevention and to increase condom usage. In addition, mobile applications, which have been the main tools for the population to contact sexual partners, should be used in programs for HIV prevention and control. Moreover, a high proportion of people who did not have timely diagnosis and treatment indicates that much more attention should be payed to HIV counseling and testing, to popularizing knowledge of HAART and to mobilizing PLWH who have not start treatment to receive HAART as early as possible. 2. Several new recombinant strains including CRF55_01B, CRF67_01B and CRF68_01B are widely epidemic in Nanjing, and have been transmitted into students. In addition, large number of unidentified 01C_like strains spread rapidly in students. Thus, urgent implementation of comprehensive control measures is necessary to monitor and curb the spread of HIV epidemic in young students. 3. The MSM among young students in Nanjing were mainly infected by non-students. The transmission linkage exists not only in the individuals diagnosed in Nanjing (intra-city), but also in the individuals diagnosed in Nanjing and other cities in Jiangsu and other provinces (inter-province). This shows that HIV-1 in young students have complex origins, and also emphasizes that the AIDS prevention in colleges should be taken into the overall consideration in general population. 4. A minority of super-spreaders indeed drive transmission networks to a significant extend. Identification and precision intervention of these individuals are necessary for curbing the spread of HIV-1 among general populations. Homosexual behaviors, recent infection and a lower rate of condom usage are contributing factors of network formation and super-spreaders. Therefore, urgent implementation of comprehensive control measures including curbing the HIV-1 epidemic seriously in MSM, proceeding HIV counseling and testing, promoting accessibility and utilization of condoms should be conducted.
学术讨论
主办单位时间地点报告人报告主题
上海市CDC 2015.09.07 上海市CDC 李小杉 Transmission Network Analysis
中国性病艾滋病防治协会 2015.11.19 上海光大会展中心国际大酒店 钟平 HIV-1分子传播网络(簇)监测研究进展
东南大学研究生校庆学术报告会 2016.05.12 东南大学公共卫生学院 李小杉 人类免疫缺陷病毒-1 CRF01_AE毒株在我国的分子传播网络分析
四川省CDC 2016.08.05 四川省CDC 李小杉 HIV-传播网络构建流程及相关软件使用介绍
中国性病艾滋病防治协会 2016.10.27 成都加州花园酒店(国际会议展览中心) 李小杉 Evolutionary Dynamics and Complicated Genetic Transmission Network Patterns of HIV-1 CRF01_AE among MSM in Shanghai, China
东南大学研究生校庆学术报告会 2017.05.12 东南大学公共卫生学院 李小杉 Multiple Introductions and Onward Transmission of HIV-1 Subtype B Strains in Shanghai, China
上海市预防医学会 2017.05.13 华亭宾馆 李小杉 高校辅导员防艾知识、态度及教育效果评价
AMERICAN ASSOCIATION of IMMUNOLOGISTS 2017.05.15 Washington,DC 李小杉 Genetic Transmission Networks Reveal the Transmission Patterns of HIV-1 CRF01_AE in China
     
学术会议
会议名称时间地点本人报告本人报告题目
中国性病艾滋病防治协会 2016.10.27 成都加州花园酒店(国际会议展览中心) Evolutionary Dynamics and Complicated Genetic Transmission Network Patterns of HIV-1 CRF01_AE among MSM in Shanghai, China
东南大学研究生校庆学术报告会 2017.5.12 东南大学公共卫生学院 Multiple Introductions and Onward Transmission of HIV-1 Subtype B Strains in Shanghai, China
     
代表作
论文名称
Nationwide Trends in Molecular Epidemiology of HIV-1 in China
Coreceptor usage of Chinese HIV-1 and impact of X4DM transmission clusters among recently infected m
Multiple introductions and onward transmission of HIV-1 subtype B strains in Shanghai, China
 
答辩委员会组成信息
姓名职称导师类别工作单位是否主席备注
浦跃朴 正高 教授 博导 东南大学
傅更锋 正高 研究员 硕导 江苏省疾病预防控制中心
喻荣彬 正高 教授 博导 南京医科大学
尹立红 正高 教授 博导 东南大学
沈孝兵 正高 教授 博导 东南大学
      
答辩秘书信息
姓名职称工作单位备注
王莉娜 副高 副教授 东南大学