Molecular Epidemiology and Natural History of SIVcpz

SIVcpz 的分子流行病学和自然史

• 批准号: 7754371
• 负责人: Beatrice H Hahn
• 金额: $ 65.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/7754371
• 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; Immune; 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; Viral; Virulence; Virus; Virus Diseases; base; disorder prevention; experience; fitness; hazard; immunopathology; mortality; nef Protein; novel; pandemic disease; pathogen; premature; public health relevance; reproductive success; success; therapeutic vaccine; transmission process; viral detection

DESCRIPTION (provided by applicant): 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 that 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. PUBLIC HEALTH RELEVANCE: HIV/AIDS ranks as one of the most important infectious diseases to have emerged in recent history. This application will define the molecular ecology and natural infection history of SIVcpz, the simian precursor of HIV-1. Elucidation of the determinants of SIV pathogenicity (or lack thereof) in natural and non-natural hosts is a high priority area in current AIDS research, since therapeutic and vaccine strategies consider amelioration of disease and prevention a desired outcome. SIVcpz infection of wild-living chimpanzees represents a critical piece in this puzzle.

描述（由申请人提供）：本次修订后的续展申请的重点仍然集中在野生黑猩猩中 SIVcpz 感染的自然史。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，并使用这些方法来描述整个赤道非洲野生猿种群中 SIVcpz 的分子流行病学特征（《自然》，2004 年；《科学》，2006 年）。我们还将流行性和非流行性 HIV-1 的起源追溯到喀麦隆南部的不同黑猩猩群落（Science 2006），在野生大猩猩中发现了 HIV-1 O 类病毒（Nature 2006），并发现 SIVcpz（与 HIV 类似） -1) 失去了其 Nef 蛋白的重要功能 (Cell 2006; PLoS Pathogens 2008)。这些和其他发现总结在 29 份出版物中（其中 3 份是自上次提交以来出版的）。我们还在贡贝国家公园的两个居住社区（人口规模约 90 人）发起了第一项 SIVcpz 自然历史研究，发现 (i) SIVcpz 患病率在过去七年中增加了一倍多，(ii) SIVcpz 感染的黑猩猩死亡率显着高于未感染的对照组（死亡风险增加 18.7 至 20.6 倍；p<0.0001），并且 (iii) 两名 SIVcpz 感染者黑猩猩死于类似艾滋病的免疫病理学特征。这些发现提供了第一个证据，证明 SIVcpz 感染在野生黑猩猩中具有致病性，因此与所有天然 SIV 感染都是非致病性的流行观点背道而驰。鉴于这些有趣的发现，我们建议扩大我们在贡贝的自然史研究，描述 SIVcpz 致病性的病毒和宿主决定因素，并确定其他病原体的合并感染是否影响 SIVcpz 发病率和死亡率。具体目标包括： 1. 将我们对 SIVcpz 的自然历史研究扩展到所有三个贡贝社区。我们将确定 SIVcpz 的患病率和发病率、垂直和水平传播的频率、SIVcpz 对生殖行为和成功的影响，以及较大黑猩猩群体中与 SIVcpz 相关的死亡率。 2. 阐明SIVcpz致病性的免疫病理学机制。我们将对研究期间死亡的所有猿类进行健康调查和寄生虫学研究，以及尸检分析。对尸检标本进行详细的免疫组织化学和病毒学分析将确定 SIVcpz 在多大程度上导致 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。我们将为选定的 SIVcpz 菌株生成感染性分子克隆，表征其复制适应性和相对毒力，并确定 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。我们将使用非侵入性方法对贡贝黑猩猩进行 STLV、ChHBV 和腺病毒筛查，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。公共卫生相关性：艾滋病毒/艾滋病是近代史上出现的最重要的传染病之一。该应用将定义 SIVcpz（HIV-1 的猿猴前体）的分子生态学和自然感染史。阐明SIV在自然和非自然宿主中致病性（或缺乏致病性）的决定因素是当前艾滋病研究的一个高度优先领域，因为治疗和疫苗策略将疾病的改善和预防视为期望的结果。野生黑猩猩的 SIVcpz 感染是这个难题的关键部分。