Molecular Epidemiology and Natural History of SIVcpz

SIVcpz 的分子流行病学和自然史

• 批准号: 8311806
• 负责人: Beatrice H Hahn
• 金额: $ 64.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311806
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenoviruses; Africa; Antibodies; Area; Autopsy; Behavior; Behavioral; Biological; Biological Process; Budgets; CD4 Positive T Lymphocytes; Cameroon; Cells; Cessation of life; Characteristics; Communicable Diseases; Communities; Consensus Sequence; Data; Detection; Development; Ecology; Epidemiology; Evaluation; Evolution; Exhibits; Floor; Frequencies; Genetic Variation; Gorilla gorilla; Grant; HIV-1; Health Surveys; Horizontal Disease Transmission; Incidence; Individual; Infection; Life; Longevity; Lymphoid Tissue; Methods; Molecular; Molecular Cloning; Molecular Epidemiology; Morbidity - disease rate; Natural History; Nature; Nucleic Acids; Outcome; Pan Genus; Parasitology; Pathogenicity; Pattern; Pongidae; Population; Population Sizes; Prevalence; Primates; Property; Prospective Studies; Publications; Publishing; Recording of previous events; Relative (related person); Reproductive Behavior; Research; Research Infrastructure; Running; SIV; Sampling; Science; Source; Specimen; T-Cell Depletion; Tanzania; Urine; Vertical Disease Transmission; Viral; Virulence; Virus; Virus Diseases; base; disorder prevention; experience; fitness; hazard; immune activation; immunopathology; mortality; nef Protein; novel; pandemic disease; pathogen; premature; reproductive success; therapeutic vaccine; transmission process; viral detection

Project Summary The focus of this revised renewal application remains centered around the natural history of SIVcpz infection in wild chimpanzees. In the previous budget period, we developed non-invasive (fecal and urine based) SIVcpz detection methods and used these to characterize the molecular epidemiology of SIVcpz in wild-living ape populations throughout equatorial Africa (Nature 2004; Science 2006). We also traced the origin of pandemic and non-pandemic HIV-1 to distinct chimpanzee communities in southern Cameroon (Science 2006), discovered HIV-1 group O-like viruses in wild gorillas (Nature 2006), and found that SIVcpz (like HIV-1) has lost an important function of its Nef protein (Cell 2006; PLoS Pathogens 2008). These and other findings are summarized in 29 publications (including 3 published since the last submission). We also initiated the first natural history study of SIVcpz in two habituated communities (population size ~90) in Gombe National Park and found that (i) SIVcpz prevalence has more than doubled over the past seven years, (ii) SIVcpz infected chimpanzees have a significantly higher mortality rate (18.7 to 20.6-fold increased death hazard; p<0.0001) than uninfected controls, and (iii) two SIVcpz infected chimpanzees died with characteristic AIDS-like immunopathology. These findings provide the first evidence that SIVcpz infection is pathogenic in wild chimpanzees, and thus run counter the prevailing view that all natural SIV infections are non-pathogenic. Given these intriguing findings, we propose to expand our natural history studies in Gombe, characterize viral and host determinants of SIVcpz pathogenicity, and determine if co-infections by other pathogens influence SIVcpz morbidity and mortality. Specific Aims include: 1. To expand our natural history studies of SIVcpz to all three Gombe communities. We will determine SIVcpz prevalence and incidence rates, frequencies of vertical and horizontal transmission, SIVcpz impact on reproductive behavior and success, as well as SIVcpz associated mortality in a larger group of chimpanzees. 2. To elucidate the immunopathological mechanisms underlying SIVcpz pathogenicity. We will conduct health surveys and parasitology studies, as well as post mortem analyses on all apes who die during the study period. Detailed immunohistochemical and virological analyses of necropsy specimens will determine to what extent SIVcpz causes CD4 T cell depletion, lymphatic tissue destruction and immune activation. 3. To elucidate the virological mechanisms underlying SIVcpz pathogenicity. We will generate infectious molecular clones for select SIVcpz strains, characterize their replication fitness and relative virulence, and determine the pattern and rate of SIVcpz evolution. 4. To determine the impact of other viral infections on chimpanzee morbidity and mortality. Using non- invasive methods, we will screen Gombe chimpanzees for STLV, ChHBV and adenoviruses and determine whether and to what extent these infections influence chimpanzee morbidity and mortality.

项目摘要 该修订后的续签应用的重点仍然围绕SIVCPZ感染的自然历史 在狂野的黑猩猩中。在上一个预算期间，我们开发了非侵入性（基于粪便和尿液） SIVCPZ检测方法，并使用它们来表征野生生命中SIVCPZ的分子流行病学 整个赤道非洲的猿类种群（自然2004；科学2006）。我们还追踪了 喀麦隆南部黑猩猩社区的大流行和非大流行HIV-1（科学 2006年），在野生大猩猩中发现了HIV-1组O样病毒（自然，2006年），发现SIVCPZ（如HIV-1） 失去了其NEF蛋白的重要功能（Cell 2006; Plos病原体2008）。这些和其他发现 总结在29个出版物中（包括自上次提交以来出版的3个）。我们还发起了第一个 SIVCPZ的自然历史研究在冈比国家公园的两个习惯社区（人口尺寸〜90） 并发现（i）SIVCPZ流行率在过去七年中翻了一番，（ii）Sivcpz 被感染的黑猩猩的死亡率明显更高（死亡增加了18.7至20.6倍 冒险; p <0.0001）比未感染的对照组，（iii）两个sivcpz感染的黑猩猩死于 特征性艾滋病样免疫病理学。这些发现提供了第一个证据，表明SIVCPZ感染是 野生黑猩猩的致病性，因此对抗所有天然SIV感染的普遍观点 非致病性。鉴于这些有趣的发现，我们建议扩大我们在Gombe的自然史研究 表征SIVCPZ致病性的病毒和宿主决定因素，并确定其他其他人的感染是否 病原体影响SIVCPZ的发病率和死亡率。具体目的包括： 1。将SIVCPZ的自然史研究扩展到所有三个Gombe社区。我们将确定 SIVCPZ患病率和发病率，垂直和水平传播的频率，SIVCPZ对 在较大的黑猩猩中，生殖行为和成功以及SIVCPZ相关的死亡率。 2。阐明SIVCPZ致病性的背后的免疫病理机制。我们将进行 健康调查和寄生虫研究，以及对研究期间死亡的所有猿类的验尸分析 时期。详细的尸检标本的免疫组织化学和病毒学分析将决定什么 SIVCPZ的程度会导致CD4 T细胞耗竭，淋巴组织破坏和免疫激活。 3。阐明SIVCPZ致病性的病毒学机制。我们将产生感染力 用于精选SIVCPZ菌株的分子克隆，表征其复制适应性和相对毒力，并且 确定SIVCPZ进化的模式和速率。 4。确定其他病毒感染对黑猩猩发病率和死亡率的影响。使用非 - 入侵方法，我们将筛选Gombe黑猩猩的STLV，CHHBV和腺病毒，并确定 这些感染是否以及在何种程度上影响黑猩猩的发病率和死亡率。